Highly active anti-neoplastic and anti-proliferative agents

ABSTRACT

This invention is in the area of improved compounds and methods for treating selected cancers and hyperproliferative disorders.

RELATED APPLICATIONS

This application is a continuation of U.S. Appl. No. 16/926,035, filedJul. 10, 2020, which is a continuation of U.S. Appl. No. 16/228,308,filed Dec. 20, 20,18, which is a continuation of U.S. Appl. No.15/713,385, filed Sep. 22, 2017; which is a continuation of U.S. Appl.No. 15/201,286, filed Jul. 1, 2016; which is a divisional of U.S. Appl.No. 14/213,784, filed on Mar. 14, 2014; which claims priority toProvisional U.S. Appl. No. 61/798,772, filed Mar. 15, 2013, provisionalU.S. Appl. No. 61/861,374, filed on Aug. 1, 2013, provisional U.S. Appl.61/911,354, filed on Dec. 3, 2013, and provisional U.S. Appl. No.61/949,795, filed on Mar. 7, 2014. The entirety of each of theseapplications is hereby incorporated by reference for all purposes.

GOVERNMENT INTEREST

This invention was made with government support under Grant No.5R44AI084284 awarded by National Institute of Allergy and InfectiousDiseases. The government has certain rights in the invention.

FIELD

This invention is in the area of improved compounds and methods fortreating selected cancers and hyperproliferative disorders.

BACKGROUND

Cancer is a group of diseases categorized by uncontrolled growth andspread. In the United States in 2013, approximately 1.6 million newcases of cancer were expected to be diagnosed, and over 500,000 peoplein the U.S. were expected to die from the disease, which is about 1,600per day. Cancer Facts and Figures 2013, American Cancer Society.

All cancers involve a malfunction of genes that control cell growth anddivision. Although all cancers share that characteristic, cancers varygreatly according to tissue or cell type, which specific genes are downor upregulated, which aspect of the cell cycle is implicated, whetherand which cell surface receptors accelerate growth, types of alteredmetabolism, and which drugs the cancer cells respond to with atherapeutically acceptable effect. Therefore, one of the key goals ofcancer research is to identify drugs that show high activity againstcertain specific target cancers. Non-cancerous cellularhyperproliferation presents a similar problem.

Lymphoid neoplasms are broadly categorized into precursor lymphoidneoplasms and mature T-cell, B-cell or natural killer cell (NK)neoplasms. Chronic leukemias are those likely to exhibit primarymanifestations in blood and bone marrow, whereas lymphomas are typicallyfound in extramedullary sites, with secondary events in the blood orbone. Some mature B-cell disorders exhibit dominant immunosecretorymanifestations.

Over 79,000 new cases of lymphoma were estimated in 2013. Lymphoma is acancer of lymphocytes, which are a type of white blood cell. Lymphomasare categorized as Hodgkin or non-Hodgkin. Over 48,000 new cases ofleukemias were expected in 2013. They are classified into four maingroups according to cell type and rate of growth: acute lymphocytic(ALL), chronic lymphocytic (CLL), acute myeloid (AML), and chronicmyeloid (CML).

WO 2012/061156 filed by Francis Tavares and assigned to G1 Therapeuticsdescribes CDK inhibitors. Also see WO 2013/148748 filed by FrancisTavares and assigned to G1 Therapeutics, directed to Lactam KinaseInhibitors.

Accordingly, there is an ongoing need for highly active compoundsagainst specific cancers and cellular hyperproliferation.

SUMMARY OF THE INVENTION

The present invention includes the use of an effective amount of acompound described herein, or its pharmaceutically acceptable salt,prodrug, or isotopic variant, optionally in a pharmaceuticalcomposition, to treat a host, typically a human, with a selected cancer,tumor, hyperproliferative condition, or an inflammatory or immunedisorder as described further herein. Some of the disclosed compoundsare highly active against T-cell proliferation and/or B-cellproliferation and/or NK-cell proliferation.

Disorders include, but are not limited to those involving T-cellproliferation, maintenance of peripheral tolerance, those involving theinappropriate differentiation of Th2 cells, maturation or survival of Tand/or B cells, natural killer cell development, or regulation ofimmunoglobulin class switching in B cells.

In one embodiment, a compound/method of the present invention is used incombination with another therapy to treat the T, B or NK abnormalcellular proliferation, cancer or disorder. The second therapy can be animmunotherapy. For example, the compound can be conjugated to anantibody, radioactive agent or other targeting agent that directs thecompound to the diseased or abnormally proliferating cell. In anotherembodiment, the compound is used in combination with anotherpharmaceutical or a biologic agent (for example an antibody) to increasethe efficacy of treatment with a combined or a synergistic approach. Inan embodiment, the compound can be used with T-cell vaccination, whichtypically involves immunization with inactivated autoreactive T cells toeliminate a pathogenic autoreactive T cell population. In anotherembodiment, the compound is used in combination with a bispecific T-cellEngager (BiTE), which is an antibody designed to simultaneously bind tospecific antigens on endogenous T cells and malignant cells, linking thetwo types of cells.

In summary, the present invention includes the following features:

-   A) Selective compounds, methods, and compositions for use as    chemotherapeutics for the treatment of T-cell cancers and other    T-cell mediated disorders;-   B) Selective compounds, methods, and composition for use as    chemotherapeutics for the treatment of B-cell cancers and other    B-cell mediated disorders;-   C) Selective compounds, methods, and compositions for use as    immunosuppressants and antiinflammatory agents;-   D) Selective compounds, methods and compositions for use against    auto-immune disorders;-   E) The compounds of Formulas I, II, III, IV, and V as described    herein, and pharmaceutically acceptable compositions, salts, and    prodrugs thereof, for use in medical therapy;-   F) The compounds of Formulas I, II, III, IV, and V as described    herein, and pharmaceutically acceptable compositions, salts, and    prodrugs thereof, for use against T-cell cancers and other T-cell    mediated disorders;-   G) The compounds of Formulas I, II, III, IV, and V as described    herein, and pharmaceutically acceptable compositions, salts, and    prodrugs thereof, for use against B-cell cancers and B-cell mediated    disorders;-   H) The compounds of Formulas I, II, III, IV, and V as described    herein, and pharmaceutically acceptable compositions, salts, and    prodrugs thereof, for use in the treatment of immune disorders or    inflammatory conditions;-   I) The compounds of Formulas I, II, III, IV, and V as described    herein, and pharmaceutically acceptable compositions, salts, and    prodrugs thereof, for use in the treatment of autoimmune disorders;-   J) Processes for the preparation of therapeutic products that    contain an effective amount of the compounds of Formulas I, II, III,    IV, and V as described herein;-   K) A method for manufacturing a medicament of Formulas I, II, III,    IV, and V intended for therapeutic use;-   L) Selective compounds, methods, and compositions for use of the    compounds of Formulas I, II, III, IV, and V in combination with one    or more other therapeutic agents; and-   M) The compounds of Formulas I, II, III, IV, and V as described    herein, and pharmaceutically acceptable compositions, salts, and    prodrugs thereof, for use in combination with another one or more    additional therapeutic agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 illustrate exemplary embodiments of R² of compounds useful inthe described invention.

FIGS. 4A-4C, 5A-5D, 6A-6C, 7A-B, and 8A-8F illustrate exemplaryembodiments of the core structure of the compounds useful in thedescribed invention.

FIG. 9 is a graph showing the cellular proliferation of SupT1 cells(human T-cell lymphoblastic leukemia) treated with PD0332991 (circles)or Compound T (Table 1; squares). The SupT1 cells were seeded in Costar(Tewksbury, Massachusetts) 3093 96 well tissue culture treated whitewalled/ clear bottom plates. A nine point dose response dilution seriesfrom 10 uM to 1 nM was performed and cell viability was determined afterfour days as indicated using the CellTiter-Glo® assay (CTG; Promega,Madison, Wisconsin, United States of America) following themanufacturer’s recommendations. Plates were read on a BioTek (Winooski,Vermont) Syngergy2 multi-mode plate reader. The Relative Light Units(RLU) were plotted as a result of variable molar concentration and datawas analyzed using Graphpad (LaJolla, California) Prism 5 statisticalsoftware to determine the IC50 for each compound.

FIG. 10 is a graph showing the cellular proliferation of SupT1 cells(human T-cell lymphoblastic leukemia) treated with Compound Q (Table 1;circles) or Compound GG (Table 1; squares). The SupT1 cells were seededin Costar (Tewksbury, Massachusetts) 3093 96 well tissue culture treatedwhite walled/ clear bottom plates. A nine point dose response dilutionseries from 10uM to 1 nM was performed and cell viability was determinedafter four days as indicated using the CellTiter-Glo® assay (CTG;Promega, Madison, Wisconsin, United States of America) following themanufacturer’s recommendations. Plates were read on a BioTek (Winooski,Vermont) Syngergy2 multi-mode plate reader. The Relative Light Units(RLU) were plotted as a result of variable molar concentration and datawas analyzed using Graphpad (LaJolla, California) Prism 5 statisticalsoftware to determine the IC50 for each compound.

DETAILED DESCRIPTION

The present invention includes compounds and methods that are highlyactive against certain cancers and hyperproliferative conditions. Inparticular, compounds and methods are provided to treat cancers andproliferative disorders of hematopoietic cells, and in particular, Tcells, B cells and NK cells. Selected active compounds are also usefulto treat inflammatory disorders, auto-immune conditions, and immunedisorders.

I. Active Compounds

In one embodiment, the invention is directed to compounds or the use ofsuch compounds of Formula I, II, III, IV, or V:

or a pharmaceutically acceptable salt thereof; wherein:

-   Z is -(CH₂)_(x)- wherein x is 1, 2, 3 or 4 or -O-(CH₂)_(z)- wherein    z is 2, 3 or 4;-   each X is independently CH or N;-   each X′ is independently, CH or N;-   X″ is independently CH₂, S or NH, arranged such that the moiety is a    stable 5-membered ring;-   R, R⁸, and R¹¹ are independently H, C₁-C₃ alkyl or haloalkyl,    cycloalkyl or cycloalkyl containing one or more heteroatoms selected    from N, O or S; -(alkylene)m- C₃-C₈ cycloalkyl,    -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-    heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(0)-NR³R⁴;    -(alkylene)_(m)-0-R⁵, -(alkylene)_(m)- S(0)_(n)-R⁵, or    -(alkylene)_(m)-S(0)n-NR³R⁴ any of which may be optionally    independently substituted with one or more R groups as allowed by    valance, and wherein two R^(x) groups bound to the same or adjacent    atoms may optionally combine to form a ring;-   each R¹ is independently aryl, alkyl, cycloalkyl or haloalkyl,    wherein each of said alkyl, cycloalkyl and haloalkyl groups    optionally includes O or N heteroatoms in place of a carbon in the    chain and two R¹′s on adjacent ring atoms or on the same ring atom    together with the ring atom(s) to which they are attached optionally    form a 3-8-membered cycle;-   y is 0, 1, 2, 3 or 4;-   R² is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl,    -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)-NR³R⁴;    -(alkylene)_(m)-C(O)-O-alkyl; -(alkylene)_(m)-O-R⁵,    -(alkylene)_(m)-S(O)_(n)-R⁵, or -(alkylene)_(m)-S(O)_(n)-NR³R⁴ any    of which may be optionally independently substituted with one or    more R^(x) groups as allowed by valance, and wherein two R^(x)    groups bound to the same or adjacent atom may optionally combine to    form a ring and wherein m is 0 or 1 and n is 0, 1 or 2;-   R³ and R⁴ at each occurrence are independently:    -   (i) hydrogen or    -   (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl,        cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl        any of which may be optionally independently substituted with        one or more R^(x) groups as allowed by valance, and wherein two        R^(x) groups bound to the same or adjacent atom may optionally        combine to form a ring; or R³ and R⁴ together with the nitrogen        atom to which they are attached may combine to form a        heterocyclo ring optionally independently substituted with one        or more R^(x) groups as allowed by valance, and wherein two        R^(x) groups bound to the same or adjacent atom may optionally        combine to form a ring;-   R⁵ and R⁵* at each occurrence is:    -   (i) hydrogen or    -   (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,        heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or        heteroarylalkyl any of which may be optionally independently        substituted with one or more R^(x) groups as allowed by valance;-   R^(x) at each occurrence is independently, halo, cyano, nitro, oxo,    alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl, heterocycloalkyl, -(alkylene)_(m)-OR⁵,    -(alkylene)_(m)-O-alkylene-OR⁵, -(alkylene)_(m)-S(O)_(n)-R⁵,    -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-CN, -(alkylene)_(m)-C(O)-R⁵,    -(alkylene)_(m)-C(S)-R⁵, -(alkylene)_(m)-C(O)-OR⁵,    -(alkylene)_(m)-O-C(O)-R⁵, -(alkylene)_(m)-C(S)-OR⁵,    -(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴,    -(alkylene)_(m)-C(S)-NR³R⁴, -(alkylene)_(m)-N(R³)-C(O)-NR³R⁴,    -(alkylene)_(m)-N(R³)-C(S)-NR³R⁴, -(alkylene)_(m)-N(R³)-C(O)-R⁵,    -(alkylene)_(m)-N(R³)-C(S)-R⁵, -(alkylene)_(m)-O-C(O)-NR³R⁴,    -(alkylene)_(m)-O-C(S)-NR³R⁴, -(alkylene)_(m)-SO₂-NR³R⁴,    -(alkylene)_(m)-N(R³)-SO₂-R⁵, -(alkylene)_(m)-N(R³)-SO₂-NR³R⁴,    -(alkylene)_(m)-N(R³)-C(O)-OR⁵) -(alkylene)_(m)-N(R³)-C(S)-OR⁵, or    -(alkylene)_(m)-N(R³)-SO₂-R⁵; wherein:    -   said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups        may be further independently substituted with one or more        -(alkylene)_(m)-CN, -(alkylene)_(m)-OR⁵*,        -(alkylene)_(m)-S(O)_(n-)R⁵*, -(alkylene)_(m)-NR³*R⁴*,        -(alkylene)_(m)-C(O)-R⁵*, -(alkylene)_(m)-C(=S)R⁵*,        -(alkylene)_(m)-C(=O)O R⁵*, -(alkylene)_(m)-OC(=O)R⁵*,        -(alkylene)_(m)-C(S)-OR⁵*, -(alkylene)_(m)-C(O)-NR³*R⁴*,        -(alkylene)_(m)-C(S)-NR³*R⁴*,        -(alkylene)_(m)-N(R³*)-C(O)-NR³*R⁴*,        -(alkylene)_(m)-N(R³*)-C(S)-NR³*R⁴*,        -(alkylene)_(m)-N(R³*)-C(O)-R⁵*,        -(alkylene)_(m)-N(R³*)-C(S)-R⁵*, -(alkylene)_(m)-O-C(O)-NR³*R⁴*,        -(alkylene)_(m)-O-C(S)-NR³*R⁴*, -(alkylene)_(m)-SO₂-NR³*R⁴*,        -(alkylene)_(m)-N(R³*)-SO₂-R⁵*,        -(alkylene)_(m)-N(R³*)-SO₂-NR³*R⁴*,        -(alkylene)_(m)-N(R³*)-C(O)-OR⁵*,        -(alkylene)_(m)-N(R³*)-C(S)-OR⁵*, or        -(alkylene)_(m)-N(R³*)-SO₂-R⁵*,    -   n is 0, 1 or 2, and    -   m is 0 or 1;-   R³* and R⁴* at each occurrence are independently:    -   (i) hydrogen or    -   (ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl,        heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or        heteroarylalkyl any of which may be optionally independently        substituted with one or more R^(x) groups as allowed by valance;        or R³* and R⁴* together with the nitrogen atom to which they are        attached may combine to form a heterocyclo ring optionally        independently substituted with one or more R^(x) groups as        allowed by valance; and-   R⁶ is H or lower alkyl, -(alkylene)m-heterocyclo,    -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴,    -(alkylene)_(m)-C(0)-NR³R⁴; -(alkylene)_(m),-0-R⁵,    -(alkylene)_(m)-S(O)_(n)-R⁵, or -(alkylene)_(m)-S(0)_(n)-NR³R⁴ any    of which may be optionally independently substituted with one or    more R^(x) groups as allowed by valance, and wherein two R^(x)    groups bound to the same or adjacent atoms may optionally combine to    form a ring; and-   R¹⁰ is (i) NHR^(A), wherein R^(A) is unsubstituted or substituted    C₁-C₈ alkyl, cycloalkylalkyl, or -TT-RR, C₁-C₈ cycloalkyl or    cycloalkyl containing one or more heteroatoms selected from N, O,    and S; TT is an unsubstituted or substituted C₁-C₈ alkyl or C₃-C₈    cycloalkyl linker; and RR is a hydroxyl, unsubstituted or    substituted C₁-C₆ alkoxy, amino, unsubstituted or substituted C₁-C₆    alkylamino, unsubstituted or substituted di-C₁-C₆ alkylamino,    unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or    substituted heteroaryl comprising one or two 5- or 6-member rings    and 1-4 heteroatoms selected from N, O and S, unsubstituted or    substituted C₃-C₁₀ carbocycle, or unsubstituted or substituted    heterocycle comprising one or two 5- or 6-member rings and 1-4    heteroatoms selected from N, O and S; or (ii) -C(O)-R¹² or    -C(O)O-R¹³, wherein R¹² is NHR^(A) or-   R^(A) and R¹³ is R^(A);-   or a pharmaceutically acceptable salt, prodrug or isotopic variant,    for example, partically or fully deuterated form thereof.

In some aspects, the compound is of Formula I or Formula II and R⁶ isabsent.

In some aspects, the compound is of Formula III:

and the variables are as defined for compounds of Formulae I and II andpharmaceutically acceptable salts thereof.

In some aspects, R^(x) is not further substituted.

In some aspects, R² is -(alkylene)_(m)-heterocyclo,-(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴,-(alkylene)_(m)-C(O)-NR³R⁴; -(alkylene)_(m)-O-R⁵,-(alkylene)_(m)-S(O)_(n)-R⁵, or -(alkylene)_(m)-S(O)_(n)-NR³R⁴ any ofwhich may be optionally independently substituted with one or more R^(x)groups as allowed by valance, and wherein two R^(x) groups bound to thesame or adjacent atom may optionally combine to form a ring and whereinm is 0 or 1 and n is 0, 1 or 2.

In some aspects, R⁸ is hydrogen or C₁-C₃ alkyl.

In some aspects, R is hydrogen or C₁-C₃ alkyl.

In some aspects, R² is -(alkylene)_(m)-heterocyclo,-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)-NR³R⁴,-(alkylene)_(m)-C(O)-O-alkyl or -(alkylene)_(m)-OR⁵ any of which may beoptionally independently substituted with one or more R^(x) groups asallowed by valance, and wherein two R^(x) groups bound to the same oradjacent atom may optionally combine to form a ring.

In some aspects, R² is -(alkylene)_(m)-heterocyclo,-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)-NR³R⁴,-(alkylene)_(m)-C(O)-O-alkyl or -(alkylene)_(m)-OR⁵ without furthersubstitution.

In some aspects, m in R² is 1. In a further aspect, the alkylene in R²is methylene.

In some aspects, R² is

wherein:

-   R²* is a bond, alkylene, -(alkylene)_(m)-O-(alkylene)_(m)-,    -(alkylene)_(m)-C(O)-(alkylene)_(m)-,    -(alkylene)_(m)-S(O)₂-(alkylene)_(m)- and    -(alkylene)_(m)-NH-(alkylene)_(m)- wherein each m is independently 0    or 1;-   P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl    group;-   each R^(x1) is independently    -(alkylene)_(m)-(C(O))_(m)-(alkylene)_(m)-(N(R^(N)))_(m)-(alkyl)_(m)    wherein each m is independently 0 or 1 provided at least one m is 1,    -(C(O))-O-alkyl, -(alkylene)_(m)-cycloalkyl wherein m is 0 or 1,    -N(R^(N))-cycloalkyl, -C(O)-cycloalkyl, -(alkylene)_(m)-heterocyclyl    wherein m is 0 or 1, or -N(R^(N))-heterocyclyl,    -C(O)-heterocyclyl,-S(O)₂-(alkylene)_(m) wherein m is 1 or 2,    wherein:    -   R^(N) is H, C₁ to C₄ alkyl or C₁ to C₆ heteroalkyl, and    -   wherein two R^(x1) can, together with the atoms to which they        attach on P, which may be the    -   same atom, form a ring; and-   t is 0, 1 or 2.

In some aspects, each R^(x1) is only optionally substituted byunsubstituted alkyl, halogen or hydroxy.

In some aspects, R^(x1) is hydrogen or unsubstituted C₁-C₄ alkyl.

In some aspects, at least one R^(x1) is -(alkylene)_(m)-heterocyclylwherein m is 0 or 1.

In some aspects, R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group.

In some aspects, R² is

In some aspects, R² is

In some aspects, R² is

wherein:

-   R²* is a bond, alkylene, -(alkylene)_(m)-O-(alkylene)_(m)-,    -(alkylene)_(m)-C(O)-(alkylene)_(m)-,    -(alkylene)_(m)-S(O)₂-(alkylene)_(m)- and    -(alkylene)_(m)-NH-(alkylene)_(m)- wherein each m is independently 0    or 1;-   P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl    group;-   P1 is a 4- to 6-membered monocyclic saturated heterocyclyl group;-   each R^(x2) is independently hydrogen or alkyl; and-   s is 0, 1 or 2.

In some aspects, R² is

In some aspects, P1 includes at least one nitrogen.

In some aspects, any alkylene in R²* in any previous aspect is notfurther substituted.

In some aspects, R² is selected from the structures depicted in FIGS.1-3 .

In some aspects, R² is

In some aspects, the compound has general Formula I and morespecifically one of the general structures in FIGS. 4-8 wherein thevariables are as previously defined.

In some aspects, the compound has general Formula Ia:

wherein R¹, R², R and y are as previously defined.

In some embodiments, the compound has Formula Ia and R is alkyl.

In some embodiments, the compound has Formula Ia and R is H.

In some embodiments, the compound has Formula Ia and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group and R²*, R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ia and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or unsubstituted C₁-C₄ alkyl andR²* is as previously defined.

In some embodiments, the compound has Formula Ib:

wherein R² and R are as previously defined.

In some embodiments, the compound has Formula Ib and R is alkyl.

In some embodiments, the compound has Formula Ib and R is H.

In some embodiments, the compound has Formula Ib and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group and R²*, R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ib and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R²* is aspreviously defined.

In some embodiments, the compound has Formula Ic:

wherein R² and R are as previously defined.

In some embodiments, the compound has Formula Ic and R is alkyl.

In some embodiments, the compound has Formula Ic and R is H.

In some embodiments, the compound has Formula Ic and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group and R²*, R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ic and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R²* is aspreviously defined.

In some embodiments, the compound has Formula Id:

wherein R² and R are as previously defined.

In some embodiments, the compound has Formula Id and R is alkyl.

In some embodiments, the compound has Formula Id and R is H.

In some embodiments, the compound has Formula Id and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group and R²*, R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Id and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R²* is aspreviously defined.

In some embodiments, the compound has Formula Ie:

In some embodiments, the compound has Formula Ie and R is alkyl.

In some embodiments, the compound has Formula Ie and R is H.

In some embodiments, the compound has Formula Ie and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group and R²*, R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ie and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R²* is aspreviously defined.

In some embodiments, the compound has Formula If:

In some embodiments, the compound has Formula If and R is alkyl.

In some embodiments, the compound has Formula If and R is H.

In some embodiments, the compound has Formula If and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group and R²*, R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula If and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R²* is aspreviously defined.

In some embodiments, the compound has Formula Ig:

In some embodiments, the compound has Formula Ig and R is alkyl.

In some embodiments, the compound has Formula Ig and R is H.

In some embodiments, the compound has Formula Ig and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group and R²*, R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ig and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R²* is aspreviously defined.

In some embodiments, the compound has Formula Ih:

In some embodiments, the compound has Formula Ih and R is alkyl.

In some embodiments, the compound has Formula Ih and R is H.

In some embodiments, the compound has Formula Ih and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group and R²*, R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ih and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R²* is aspreviously defined.

In some embodiments, the compound has Formula Ii:

In some embodiments, the compound has Formula Ii and R is alkyl.

In some embodiments, the compound has Formula Ii and R is H.

In some embodiments, the compound has Formula Ii and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group and R²*, R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ii and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R²* is aspreviously defined.

In some embodiments, the compound has Formula Ij:

In some embodiments, the compound has Formula Ij and R is alkyl.

In some embodiments, the compound has Formula Ij and R is H.

In some embodiments, the compound has Formula Ij and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group.

In some embodiments, the compound has Formula Ij and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some embodiments, the compound has Formula Ij and R is H, and both Xare N.

In some embodiments, the compound has the structure:

In some embodiments, the compound has Formula Ik and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group.

In some embodiments, the compound has Formula Ik and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some embodiments, the compound has Formula Il:

In some embodiments, the compound has Formula Il and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group.

In some embodiments, the compound has Formula Il and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some embodiments, the compound has Formula Im:

In some embodiments, the compound has Formula Im and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group.

In some embodiments, the compound has Formula Im and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some embodiments, the compound has Formula IIa:

In some embodiments, the compound has Formula IIa and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group.

In some embodiments, the compound has Formula IIa and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some embodiments, the compound has Formula IIb:

In some embodiments, the compound has Formula Im and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group.

In some embodiments, the compound has Formula Im and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturatedheterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some aspects, the active compound is:

Isotopic Substitution

The present invention includes compounds and the use of compounds withdesired isotopic substitutions of atoms, at amounts above the naturalabundance of the isotope, i.e., enriched. Isotopes are atoms having thesame atomic number but different mass numbers, i.e., the same number ofprotons but a different number of neutrons. By way of general exampleand without limitation, isotopes of hydrogen, for example, deuterium(²H) and tritium (³H) may be used anywhere in described structures.Alternatively or in addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, maybe used. A preferred isotopic substitution is deuterium for hydrogen atone or more locations on the molecule to improve the performance of thedrug. The deuterium can be bound in a location of bond breakage duringmetabolism (an α-deuterium kinetic isotope effect) or next to or nearthe site of bond breakage (a β-deuterium kinetic isotope effect).

Substitution with isotopes such as deuterium can afford certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements. Substitution of deuterium for hydrogen at a site ofmetabolic break down can reduce the rate of or eliminate the metabolismat that bond. At any position of the compound that a hydrogen atom maybe present, the hydrogen atom can be any isotope of hydrogen, includingprotium (¹H), deuterium (²H) and tritium (³H). Thus, reference herein toa compound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

The term “isotopically-labeled” analog refers to an analog that is a“deuterated analog”, a “¹³C-labeled analog,” or a“deuterated/¹³C-labeled analog.” The term “deuterated analog” means acompound described herein, whereby a H-isotope, i.e., hydrogen/protium(¹H), is substituted by a H-isotope, i.e., deuterium (²H). Deuteriumsubstitution can be partial or complete. Partial deuterium substitutionmeans that at least one hydrogen is substituted by at least onedeuterium. In certain embodiments, the isotope is 90, 95 or 99% or moreenriched in an isotope at any location of interest. In some embodimentsit is deuterium that is 90, 95 or 99% enriched at a desired location.

Further specific compounds that fall within the present invention andthat can be used in the disclosed methods of treatment and compositionsinclude the structures listed in Table 1 below.

TABLE 1 Exemplary Non-limiting Structures of Anti-Neoplastic andAnti-Proliferative Agents Structure Reference Structure A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

Y

Z

AA

BB

CC

DD

EE

FF

GG

HH

II

JJ

KK

LL

MM

NN

OO

PP

QQ

RR

SS

TT

UU

VV

WW

XX

YY

ZZ

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

III

JJJ

KKK

LLL

MMM

NNN

OOO

PPP

QQQ

RRR

SSS

TTT

UUU

VVV

WWW

XXX

Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. As used in the specification and the appended claims, thesingular forms “a,” “an” and “the” include plural referents unless thecontext clearly dictates otherwise. Definition of standard chemistryterms may be found in reference works, including Carey and Sundberg(2007) Advanced Organic Chemistry 5^(th) Ed. Vols. A and B, SpringerScience+Business Media LLC, New York. The practice of the presentinvention will employ, unless otherwise indicated, conventional methodsof synthetic organic chemistry, mass spectroscopy, preparative andanalytical methods of chromatography, protein chemistry, biochemistry,recombinant DNA techniques and pharmacology. Conventional methods oforganic chemistry include those included in March’s Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Edition, M.B.Smith and J. March, John Wiley & Sons, Inc., Hoboken, NJ, 2007.

The term “alkyl,” either alone or within other terms such as “haloalkyl”and “alkylamino,” embraces linear or branched radicals having one toabout twelve carbon atoms. “Lower alkyl” radicals have one to about sixcarbon atoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,hexyl and the like. The term “alkylene” embraces bridging divalentlinear and branched alkyl radicals. Examples include methylene,ethylene, propylene, isopropylene and the like.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twelve carbon atoms.“Lower alkenyl” radicals having two to about six carbon atoms. Examplesof alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyland 4-methylbutenyl. The terms “alkenyl” and “lower alkenyl,” embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

The term “alkynyl” denotes linear or branched radicals having at leastone carbon-carbon triple bond and having two to about twelve carbonatoms. “Lower alkynyl” radicals having two to about six carbon atoms.Examples of such radicals include propargyl, butynyl, and the like.

Alkyl, alkenyl, and alkynyl radicals may be optionally substituted withone or more functional groups such as halo, hydroxy, nitro, amino,cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.

The term “alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino”where amino groups are independently substituted with one alkyl radicaland with two alkyl radicals, respectively. “Lower alkylamino” radicalshave one or two alkyl radicals of one to six carbon atoms attached to anitrogen atom. Suitable alkylamino radicals may be mono or dialkylaminosuch as N-methylamino, N-ethylamino, N.N-dimethylamino, N,N-diethylaminoand the like.

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with one or more halo as definedabove. Examples include monohaloalkyl, dihaloalkyl and polyhaloalkylradicals including perhaloalkyl. A monohaloalkyl radical, for oneexample, may have an iodo, bromo, chloro or fluoro atom within theradical. Dihalo and polyhaloalkyl radicals may have two or more of thesame halo atoms or a combination of different halo radicals. “Lowerhaloalkyl” embraces radicals having 1-6 carbon atoms. Examples ofhaloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Perfluoroalkyl” means an alkyl radical having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one or two rings wherein such rings may be attachedtogether in a fused manner. The term “aryl” embraces aromatic radicalssuch as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. Morepreferred aryl is phenyl. Said “aryl” group may have 1 or moresubstituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro,cyano, alkoxy, lower alkylamino, and the like. An aryl group may beoptionally substituted with one or more functional groups such as halo,hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycloand the like.

The term “heterocyclyl” (or “heterocyclo”) embraces saturated, andpartially saturated heteroatom-containing ring radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen.Heterocyclic rings comprise monocyclic 6-8 membered rings, as well as5-16 membered bicyclic ring systems (which can include bridged fused andspiro-fused bicyclic ring systems). It does not include rings containing-O-O-.-O-S- or -S-S- portions. Said “heterocyclyl” group may have 1 to 3substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl,lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino, and the like.

Examples of saturated heterocyclo groups include saturated 3- to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl,and the like.

Particular examples of partially saturated and saturated heterocyclogroups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl, and the like.

Heterocyclo groups also includes radicals where heterocyclic radicalsare fused/condensed with aryl radicals: unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl]; and saturated, partially unsaturated and unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms[e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl anddihydrobenzofuryl].

The term “heteroaryl” denotes aryl ring systems that contain one or moreheteroatoms selected from the group O, N and S, wherein the ringnitrogen and sulfur atom(s) are optionally oxidized, and nitrogenatom(s) are optionally quarternized. Examples include unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, IH-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated5- to 6-membered heteromonocyclic group containing an oxygen atom, forexample, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-memberedheteromonocyclic group containing a sulfur atom, for example, 2-thienyl,3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example,oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heteroarylalkyl” denotes alkyl radicals substituted with aheteroaryl group. Examples include pyridylmethyl and thienylethyl.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals -SO₂-.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes -C(O)-OH.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes -C(O)-.

The term “aminocarbonyl” denotes an amide group of the Formula-C(O)-NH₂.

The terms “heterocycloalkyl” embrace heterocyclic-substituted alkylradicals. Examples include piperidylmethyl and morpholinylethyl.

The term “arylalkyl” embraces aryl-substituted alkyl radicals. Examplesinclude benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkylmay be additionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

The term “cycloalkyl” includes saturated carbocyclic groups of 3 to 10carbons. Lower cycloalkyl groups include C₃-C₆ rings. Examples includecyclopentyl, cyclopropyl, and cyclohexyl. Cycloalkyl groups may beoptionally substituted with one or more functional groups such as halo,hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycloand the like.

The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkylradicals. “Lower cycloalkylalkyl” radicals are cycloalkyl radicalsattached to alkyl radicals having one to six carbon atoms. Examples ofinclude cyclohexylmethyl. The cycloalkyl in said radicals may beadditionally substituted with halo, alkyl, alkoxy and hydroxy.

The term “cycloalkenyl” includes carbocyclic groups having one or morecarbon-carbon double bonds including “cycloalkyldienyl” compounds.Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl andcycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicatedcomponent but not excluding other elements.

The term “oxo” as used herein contemplates an oxygen atom attached witha double bond.

The term “nitro” as used herein contemplates —NO₂.

The term “cyano” as used herein contemplates —CN.

As used herein, the term “prodrug” means a compound which whenadministered to a host in vivo is converted into the parent drug. Asused herein, the term “parent drug” means any of the presently describedchemical compounds that are useful to treat any of the disordersdescribed herein, or to control or improve the underlying cause orsymptoms associated with any physiological or pathological disorderdescribed herein in a host, typically a human. Prodrugs can be used toachieve any desired effect, including to enhance properties of theparent drug or to improve the pharmaceutic or pharmacokinetic propertiesof the parent. Prodrug strategies exist which provide choices inmodulating the conditions for in vivo generation of the parent drug, allof which are deemed included herein. Nonlimiting examples of prodrugstrategies include covalent attachment of removable groups, or removableportions of groups, for example, but not limited to acylation,phosphorylation, phosphonylation, phosphoramidate derivatives,amidation, reduction, oxidation, esterification, alkylation, othercarboxy derivatives, sulfoxy or sulfone derivatives, carbonylation oranhydride, among others.

The term “host” refers to an individual, preferably a mammal such as ahuman. The term “host” can include domesticated animals, such as cats,dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.),laboratory animals (e.g., mouse, monkey, rabbit, rat, guinea pig, etc.)and birds.

Method of Treatment of Selected Cancer, Tumors, HyperproliferativeConditions, and Inflammatory and Immune Disorders

In certain aspects, the invention includes the use of an effectiveamount of a compound described herein, or its pharmaceuticallyacceptable salt, prodrug or isotopic variant optionally in apharmaceutical composition, to treat a host, typically a human, with aselected cancer, tumor, hyperproliferative condition or an inflammatoryor immune disorder. Some of the disclosed compounds are highly activeagainst T-cell proliferation. Given the paucity of drugs for T-cellcancers and abnormal proliferation, the identification of such usesrepresents a substantial improvement in the medical therapy for thesediseases.

Abnormal proliferation of T-cells, B-cells, and/or NK-cells can resultin a wide range of diseases such as cancer, proliferative disorders andinflammatory/immune diseases. A host, for example a human, afflictedwith any of these disorders can be treated with an effective amount of acompound as described herein to achieve a decrease in symptoms (apalliative agent) or a decrease in the underlying disease (a diseasemodifying agent).

Examples include T-cell or NK-cell lymphoma, for example, but notlimited to: peripheral T-cell lymphoma; anaplastic large cell lymphoma,for example anaplastic lymphoma kinase (ALK) positive, ALK negativeanaplastic large cell lymphoma, or primary cutaneous anaplastic largecell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma,for example mycosis fungoides, Sezary syndrome, primary cutaneousanaplastic large cell lymphoma, primary cutaneous CD30+ T-celllymphoproliferative disorder; primary cutaneous aggressiveepidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneousgamma-delta T-cell lymphoma; primary cutaneous small/medium CD4+ T-celllymphoma, and lymphomatoid papulosis; Adult T-cell Leukemia/Lymphoma(ATLL); Blastic NK-cell Lymphoma; Enteropathy-type T-cell lymphoma;Hematosplenic gamma-delta T-cell Lymphoma; Lymphoblastic Lymphoma; NasalNK/T-cell Lymphomas; Treatment-related T-cell lymphomas; for examplelymphomas that appear after solid organ or bone marrow transplantation;T-cell prolymphocytic leukemia; T-cell large granular lymphocyticleukemia; Chronic lymphoproliferative disorder of NK-cells; AggressiveNK cell leukemia; Systemic EBV+ T-cell lymphoproliferative disease ofchildhood (associated with chronic active EBV infection); Hydroavacciniforme-like lymphoma; Adult T-cell leukemia/ lymphoma;Enteropathy-associated T-cell lymphoma; Hepatosplenic T-cell lymphoma;or Subcutaneous panniculitis-like T-cell lymphoma.

In one embodiment, a compound disclosed herein, or its salt, prodrug, orisotopic variant can be used in an effective amount to treat a host, forexample a human, with a lymphoma or lymphocytic or myelocyticproliferation disorder or abnormality. For example, the compounds asdescribed herein can be administered to a host suffering from a HodgkinLymphoma or a Non-Hodgkin Lymphoma. For example, the host can besuffering from a Non-Hodgkin Lymphoma such as, but not limited to: anAIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma;Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt’sLymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma);Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; CutaneousT-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-CellLymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-CellLymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal ZoneLymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-CellLymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias;Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; orWaldenstrom’s Macroglobulinemia.

Alternatively, a compound disclosed herein, or its salt, prodrug, orisotopic variant can be used in an effective amount to treat a host, forexample a human, with a Hodgkin Lymphoma, such as, but not limited to:Nodular Sclerosis Classical Hodgkin’s Lymphoma (CHL); Mixed CellularityCHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; LymphocytePredominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL.

Alternatively, a compound disclosed herein, or its salt, prodrug, orisotopic variant can be used in an effective amount to treat a host, forexample a human with a specific B-cell lymphoma or proliferativedisorder such as, but not limited to: multiple myeloma; Diffuse large Bcell lymphoma; Follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT); Small cell lymphocytic lymphoma;Mediastinal large Bcell lymphoma; Nodal marginal zone B cell lymphoma (NMZL); Splenicmarginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma;Primary effusion lymphoma; or Lymphomatoid granulomatosis;; B-cellprolymphocytic leukemia; Hairy cell leukemia; Splenic lymphoma/leukemia,unclassifiable; Splenic diffuse red pulp small B-cell lymphoma; Hairycell leukemia-variant; Lymphoplasmacytic lymphoma; Heavy chain diseases,for example, Alpha heavy chain disease, Gamma heavy chain disease, Muheavy chain disease; Plasma cell myeloma; Solitary plasmacytoma of bone;Extraosseous plasmacytoma; Primary cutaneous follicle center lymphoma; Tcell/histiocyte rich large B-cell lymphoma; DLBCL associated withchronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly;Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneousDLBCL, leg type; ALK+ large B-cell lymphoma; Plasmablastic lymphoma;Large B-cell lymphoma arising in HHV8-associated multicentric; Castlemandisease; B-cell lymphoma, unclassifiable, with features intermediatebetween diffuse large B-cell lymphoma; or B-cell lymphoma,unclassifiable, with features intermediate between diffuse large B-celllymphoma and classical Hodgkin lymphoma.

In one embodiment, a compound disclosed herein, or its salt, prodrug, orisotopic variant can be used in an effective amount to treat a host, forexample a human with leukemia. For example, the host may be sufferingfrom an acute or chronic leukemia of a lymphocytic or myelogenousorigin, such as, but not limited to: Acute lymphoblastic leukemia (ALL);Acute myelogenous leukemia (AML); Chronic lymphocytic leukemia (CLL);Chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia(JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (asubtype of AML); large granular lymphocytic leukemia; or Adult T-cellchronic leukemia. In one embodiment, the patient suffers from an acutemyelogenous leukemia, for example an undifferentiated AML (M0);myeloblastic leukemia (M1; with/without minimal cell maturation);myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia(M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant witheosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); ormegakaryoblastic leukemia (M7).

In another embodiment, a compound disclosed herein, or its salt,prodrug, or isotopic variant can be used in an effective amount to treata host, for example a human with an autoimmune disorder. Examplesinclude, but are not limited to: Acute disseminated encephalomyelitis(ADEM); Addison’s disease; Agammaglobulinemia; Alopecia areata;Amyotrophic lateral sclerosis (Also Lou Gehrig’s disease; Motor NeuronDisease); Ankylosing Spondylitis; Antiphospholipid syndrome;Antisynthetase syndrome; Atopic allergy; Atopic dermatitis; Autoimmuneaplastic anemia; Autoimmune arthritis; Autoimmune cardiomyopathy;Autoimmune enteropathy; Autoimmune granulocytopenia; Autoimmunehemolytic anemia; Autoimmune hepatitis; Autoimmune hypoparathyroidism;Autoimmune inner ear disease; Autoimmune lymphoproliferative syndrome;Autoimmune myocarditis; Autoimmune pancreatitis; Autoimmune peripheralneuropathy; Autoimmune ovarian failure; Autoimmune polyendocrinesyndrome; Autoimmune progesterone dermatitis; Autoimmunethrombocytopenic purpura; Autoimmune thyroid disorders; Autoimmuneurticarial; Autoimmune uveitis; Autoimmune vasculitis; Balo disease/Baloconcentric sclerosis; Behçet’s disease; Berger’s disease; Bickerstaffsencephalitis; Blau syndrome; Bullous pemphigoid; Cancer; Castleman’sdisease; Celiac disease; Chagas disease; Chronic inflammatorydemyelinating polyneuropathy; Chronic inflammatory demyelinatingpolyneuropathy; Chronic obstructive pulmonary disease; Chronic recurrentmultifocal osteomyelitis; Churg-Strauss syndrome; Cicatricialpemphigoid; Cogan syndrome; Cold agglutinin disease; Complementcomponent 2 deficiency; Contact dermatitis; Cranial arteritis; CRESTsyndrome; Crohn’s disease; Cushing’s Syndrome; Cutaneousleukocytoclastic angiitis; Dego’s disease; Dercum’s disease; Dermatitisherpetiformis; Dermatomyositis; Diabetes mellitus type 1; Diffusecutaneous systemic sclerosis; Discoid lupus erythematosus; Dressler’ssyndrome; Drug-induced lupus; Eczema; Endometriosis; Enthesitis-relatedarthritis; Eosinophilic fasciitis; Eosinophilic gastroenteritis;Eosinophilic pneumonia; Epidermolysis bullosa acquisita; Erythemanodosum; Erythroblastosis fetalis; Essential mixed cryoglobulinemia;Evan’s syndrome; Extrinsic and intrinsic reactive airways disease(asthma); Fibrodysplasia ossificans progressive; Fibrosing alveolitis(or Idiopathic pulmonary fibrosis); Gastritis; Gastrointestinalpemphigoid; Glomerulonephritis; Goodpasture’s syndrome; Graves’ disease;Guillain-Barre syndrome (GBS); Hashimoto’s encephalopathy; Hashimoto’sthyroiditis; Hemolytic anemia; Henoch-Schonlein purpura; Herpesgestationis (Gestational Pemphigoid); Hidradenitis suppurativa;Hughes-Stovin syndrome; Hypogammaglobulinemia; Idiopathic inflammatorydemyelinating diseases; Idiopathic pulmonary fibrosis; Idiopathicthrombocytopenic purpura; IgA nephropathy; Immune glomerulonephritis;Immune nephritis; Immune pneumonitis; Inclusion body myositis;inflammatory bowel disease; Interstitial cystitis; Juvenile idiopathicarthritis aka Juvenile rheumatoid arthritis; Kawasaki’s disease;Lambert-Eaton myasthenic syndrome; Leukocytoclastic vasculitis; Lichenplanus; Lichen sclerosus; Linear IgA disease (LAD); Lupoid hepatitis akaAutoimmune hepatitis; Lupus erythematosus; Majeed syndrome; microscopicpolyangiitis; Miller-Fisher syndrome; mixed connective tissue disease;Morphea; Mucha-Habermann disease aka Pityriasis lichenoides etvarioliformis acuta; Multiple sclerosis; Myasthenia gravis; Myositis;Ménière’s disease; Narcolepsy; Neuromyelitis optica (also Devic’sdisease); Neuromyotonia; Occular cicatricial pemphigoid; Opsoclonusmyoclonus syndrome; Ord’s thyroiditis; Palindromic rheumatism; PANDAS(pediatric autoimmune neuropsychiatric disorders associated withstreptococcus); Paraneoplastic cerebellar degeneration; Paroxysmalnocturnal hemoglobinuria (PNH); Parry Romberg syndrome; Pars planitis;Parsonage-Turner syndrome; Pemphigus vulgaris; Perivenousencephalomyelitis; Pernicious anaemia; POEMS syndrome; Polyarteritisnodosa; Polymyalgia rheumatic; Polymyositis; Primary biliary cirrhosis;Primary sclerosing cholangitis; Progressive inflammatory neuropathy;Psoriasis; Psoriatic arthritis; pure red cell aplasia; Pyodermagangrenosum; Rasmussen’s encephalitis; Raynaud phenomenon; Reiter’ssyndrome; relapsing polychondritis; restless leg syndrome;retroperitoneal fibrosis; rheumatic fever; rheumatoid arthritis;Sarcoidosis; Schizophrenia; Schmidt syndrome; Schnitzler syndrome;Scleritis; Scleroderma; Sclerosing cholangitis; serum sickness;Sjogren’s syndrome; Spondyloarthropathy; Stiff person syndrome; Still’sdisease; Subacute bacterial endocarditis (SBE); Susac’s syndrome;Sweet’s syndrome; Sydenham chorea; sympathetic ophthalmia; systemiclupus erythematosus; Takayasu’s arteritis; temporal arteritis (alsoknown as “giant cell arteritis”); thrombocytopenia; Tolosa-Huntsyndrome; transverse myelitis; ulcerative colitis; undifferentiatedconnective tissue disease; undifferentiated spondyloarthropathy;urticarial vasculitis; vasculitis; vitiligo; viral diseases such asEpstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1,Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV); orWegener’s granulomatosis. In some embodiments, the autoimmune disease isan allergic condition, including those from asthma, food allergies,atopic dermatitis, and rhinitis.

In yet another embodiment, a compound disclosed herein, or its salt,prodrug, or isotopic variant can be used in an effective amount to treata host, for example a human with a disease involving the immune system.In one example, a compound disclosed herein can be used to prevent organtransplant rejection (e.g., allograft rejection and graft versus hostdisease).

A compound disclosed herein, or its salt, prodrug, or isotopic variantcan be used in an effective amount to treat a host, for example a humanwith a skin disorders such as psoriasis (for example, psoriasisvulgaris), atopic dermatitis, skin rash, skin irritation, skinsensitization (e.g., contact dermatitis or allergic contact dermatitis).For example, certain substances including some pharmaceuticals whentopically applied can cause skin sensitization. In some embodiments, theskin disorder is treated by topical administration of compounds known inthe art in combination with the compounds disclosed herein.

A compound disclosed herein, or its salt, prodrug, or isotopic variantcan be used in an effective amount to treat a host, for example a humanwith a proliferative condition such as a myeloproliferative disorder(MPD), polycythemia vera (PV), essential thrombocythemia (ET), myeloidmetaplasia with myelofibrosis (MMM), chronic myelomonocytic leukemia(CMML), hypereosinophilic syndrome (HES), systemic mast cell disease(SMCD), and the like.

A compound disclosed herein, or its salt, prodrug, or isotopic variantcan be used in an effective amount to treat a host, for example a humanwith an inflammatory disorder. Example inflammatory diseases includeinflammatory diseases of the eye (e.g., iritis, uveitis, conjunctivitis,or related disease), inflammatory diseases of the respiratory tract(e.g., the upper respiratory tract including the nose and sinuses suchas rhinitis or sinusitis or the lower respiratory tract includingbronchitis, chronic obstructive pulmonary disease, and the like),inflammatory myopathy such as myocarditis, and other inflammatorydiseases.

A compound disclosed herein, or its salt, prodrug, or isotopic variantcan be used in an effective amount to treat a host, for example a humanwith an inflammatory ischemic event such as stroke or cardiac arrest.

In another embodiment, the compounds provided herein is useful for thetreatment of primary myelofibrosis, post-polycythemia veramyelofibrosis, post-essential thrombocythemia myelofibrosis, andsecondary acute myelogenous leukemia. In another embodiment, thecompounds provided herein can be used to treat patients withintermediate or high-risk myelofibrosis, including primarymyelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis. In some embodiments, the host to betreated (e.g., a human) is determined to be non-responsive or resistantto one or more therapies for myeloproliferative disorders. In aparticular embodiment, provided herein is a method of treating amyeloproliferative neoplasm in a host in need thereof, comprisingadministering to the host an effective amount of a compositioncomprising a compound described herein, or a pharmaceutically acceptablesalt thereof.

Combination Therapy

In one aspect of the invention, the compounds disclosed herein can bebeneficially administered in combination with another therapeuticregimen for beneficial, additive or synergystic effects.

In one embodiment, a compound/method of the present invention is used incombination with another therapy to treat the T, B or NK abnormalcellular proliferation including cancer or disorder. The second therapycan be an immunotherapy. As discussed in more detail below, the compoundcan be conjugated to an antibody, radioactive agent or other targetingagent that directs the compound to the diseased or abnormallyproliferating cell. In another embodiment, the compound is used incombination with another pharmaceutical or a biologic agent (for examplean antibody) to increase the efficacy of treatment with a combined or asynergistic approach. In an embodiment, the compound can be used withT-cell vaccination, which typically involves immunization withinactivated autoreactive T cells to eliminate a pathogenic autoreactiveT cell population. In another embodiment, the compound is used incombination with a bispecific T-cell Engager (BiTE), which is anantibody designed to simultaneously bind to specific antigens onendogenous T cells and malignant cells, linking the two types of cells.

In one embodiment, the additional therapy is a monoclonal antibody(MAb). Some MAbs stimulate an immune response that destroys cancercells. Similar to the antibodies produced naturally by B cells, theseMAbs “coat” the cancer cell surface, triggering its destruction by theimmune system. FDA-approved MAbs of this type include rituximab, whichtargets the CD20 antigen found on non-Hodgkin lymphoma cells, andalemtuzumab, which targets the CD52 antigen found on B-cell chroniclymphocyticleukemia (CLL) cells. Rituximab may also trigger cell death(apoptosis) directly. Another group of MAbs stimulates an anticancerimmune response by binding to receptors on the surface of immune cellsand inhibiting signals that prevent immune cells from attacking thebody’s own tissues, including cancer cells. Other MAbs interfere withthe action of proteins that are necessary for tumor growth. For example,bevacizumab targets vascular endothelial growth factor(VEGF), a proteinsecreted by tumor cells and other cells in the tumor’s microenvironmentthat promotes the development of tumor blood vessels. When bound tobevacizumab, VEGF cannot interact with its cellular receptor, preventingthe signaling that leads to the growth of new blood vessels. Similarly,cetuximab and panitumumab target the epidermal growth factor receptor(EGFR), and trastuzumab targets the human epidermal growth factorreceptor 2 (HER-2). MAbs that bind to cell surface growth factorreceptors prevent the targeted receptors from sending their normalgrowth-promoting signals. They may also trigger apoptosis and activatethe immune system to destroy tumor cells. Another group of cancertherapeutic MAbs are the immunoconjugates. These MAbs, which aresometimes called immunotoxins or antibody-drug conjugates, consist of anantibody attached to a cell-killing substance, such as a plant orbacterial toxin, a chemotherapy drug, or a radioactive molecule. Theantibody latches onto its specific antigen on the surface of a cancercell, and the cell-killing substance is taken up by the cell.FDA-approved conjugated MAbs that work this way include ⁹⁰Y- ibritumomabtiuxetan, which targets the CD20 antigen to deliver radioactiveyttrium-90 to B-cell non-Hodgkin lymphoma cells; ¹³¹I-tositumomab, whichtargets the CD20 antigen to deliver radioactive iodine-131 tonon-Hodgkin lymphoma cells; and ado-trastuzumab emtansine, which targetsthe HER-2 molecule to deliver the drug DM1, which inhibits cellproliferation, to HER-2 expressing metastatic breast cancer cells.

Immunotherapies with T cells engineered to recognize cancer cells viabispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) areparticularly promising approaches with potential to ablate both dividingand non/slow-dividing subpopulations of cancer cells.

Bispecific antibodies, by simultaneously recognizing target antigen andan activating receptor on the surface of an immune effector cell, offeran opportunity to redirect immune effector cells to kill cancer cells.The other approach is the generation of chimeric antigen receptors byfusing extracellular antibodies to intracellular signaling domains.Chimeric antigen receptor-engineered T cells are able to specificallykill tumor cells in a MHC-independent way.

General anticancer pharmaceutical agents include: Vincristine (Oncovin®)or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin orCerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosinearabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) orPEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16),Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®),Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone(Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib(Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™), Trastuzumab(Herceptin®), Pertuzumab (Perjeta™), Lapatinib (Tykerb®), Gefitinib(Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab(Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat(Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin(Panretin®), Tretinoin (Vesanoid®), Carfilizomib (Kyprolis™),Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept(Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib(Votrient®), Regorafenib (Stivarga®), and Cabozantinib (Cometriq™).

Current chemotherapeutic drugs used to treat AML are cytarabine(cytosine arabinoside or ara-C) and the anthracycline drugs (such asdaunorubicin/daunomycin, idarubicin, and mitoxantrone). Some of theother chemo drugs that may be used to treat AML include: Cladribine(Leustatin®, 2-CdA), Fludarabine (Fludara®), Topotecan, Etoposide(VP-16), 6-thioguanine (6-TG), Hydroxyurea (Hydrea®), Corticosteroiddrugs, such as prednisone or dexamethasone (Decadron®), Methotrexate(MTX), 6-mercaptopurine (6-MP), Azacitidine (Vidaza®), Decitabine(Dacogen®)

Current chemotherapeutic drugs for CLL and other lymphomas include:purine analogs such as fludarabine (Fludara®), pentostatin (Nipent®),and cladribine (2-CdA, Leustatin®), and alkylating agents, which includechlorambucil (Leukeran®) and cyclophosphamide (Cytoxan®) andbendamustine (Treanda®). Other drugs sometimes used for CLL includedoxorubicin (Adriamycin®), methotrexate, oxaliplatin, vincristine(Oncovin®), etoposide (VP-16), and cytarabine (ara-C). Other drugsinclude Rituximab (Rituxan),Obinutuzuniab (Gazyva™), Ofatumumab(Arzerra®), Alemtuzumab (Campath®) and Ibrutinib (Imbruvica™)

Current chemotherapies for CML include: Interferon, imatinib (Gleevec),the chemo drug hydroxyurea (Hydrea®), cytarabine (Ara-C), busulfan,cyclophosphamide (Cytoxan®), and vincristine (Oncovin®). Omacetaxine(Synribo®) is a chemo drug that was approved to treat CML that isresistant to some of the TKIs now in use.

CMML is now treated with Deferasirox (Exjade®), cytarabine withidarubicin, cytarabine with topotecan, and cytarabine with fludarabine,Hydroxyurea (hydroxycarbamate, Hydrea®), azacytidine (Vidaza®) anddecitabine (Dacogen®).

Erythropoietin (Epo® or Procrit®), a growth factor that promotes redblood cell production, can help avoid transfusions of red blood cells insome patients. Recently it has been found that combining erythropoietinwith a growth factor for white blood cells (G-CSF, Neupogen®, orfilgrastim) improves the patient’s response to the erythropoietin.Darbepoetin (Aranesp®) is a long-acting form of erythropoietin. It worksin the same way but can be given less often. Oprelvekin (Neumega®,interleukin-11, or IL-11) can be used to stimulate platelet productionafter chemotherapy and in some other diseases.

Therapies for multiple myeloma include Pomalidomide (Pomalyst®),Carfilzomib (Kyprolis™), Everolimus (Afinitor®), dexamethasone(Decadron), prednisone and methylprednisolone (Solu-medrol®) andhydrocortisone.

Therapies for Hodgkins disease include Brentuximab vedotin (Adcetris™):anti-CD-30, Rituximab, Adriamycin® (doxorubicin), Bleomycin,Vinblastine, Dacarbazine (DTIC).

Monoclonal antibodies for Non-Hodgkins disease include Rituximab(Rituxan®), Ibritumomab (Zevalin®), tositumomab (Bexxar®), Alemtuzumab(Campath®) (CD52 antigen), Ofatumumab (Arzerra®), Brentuximab vedotin(Adcetris®) and Lenalidomide (Revlimid®).

B-cell Lymphoma approved therapies include:

Diffuse large B-cell lymphoma: CHOP (cyclophosphamide, doxorubicin,vincristine, and prednisone), plus the monoclonal antibody rituximab(Rituxan). This regimen, known as R-CHOP, is usually given for about 6months.

Primary mediastinal B-cell lymphoma: R-CHOP

Follicular lymphoma: rituximab (Rituxan) combined with chemo, usingeither a single chemo drug (such as bendamustine or fludarabine) or acombination of drugs, such as the CHOP or CVP (cyclophosphamide,vincristine, prednisone regimens. The radioactive monoclonal antibodies,ibritumomab (Zevalin) and tositumomab (Bexxar) are also possibletreatment options. For patients who may not be able to tolerate moreintensive chemo regimens, rituximab alone, milder chemo drugs (such aschlorambucil or cyclophosphamide).

Chronic lymphocytic leukemia/small lymphocytic lymphoma: R-CHOP

Mantle cell lymphoma: fludarabine, cladribine, or pentostatin;bortezomib (Velcade) and lenalidomide (Revlimid) and ibrutinib(Imbruvica) Extranodal marginal zone B-cell lymphoma - mucosa-associatedlymphoid tissue (MALT) lymphoma: rituximab; chlorambucil or fludarabineor combinations such as CVP, often along with rituximab.

Nodal marginal zone B-cell lymphoma: rituximab (Rituxan) combined withchemo, using either a single chemo drug (such as bendamustine orfludarabine) or a combination of drugs, such as the CHOP or CVP(cyclophosphamide, vincristine, prednisone regimens. The radioactivemonoclonal antibodies, ibritumomab (Zevalin) and tositumomab (Bexxar)are also possible treatment options. For patients who may not be able totolerate more intensive chemo regimens, rituximab alone, milder chemodrugs (such as chlorambucil or cyclophosphamide).

Splenic marginal zone B-cell lymphoma: rituximab; patients with Hep C –anti-virals

Burkitt lymphoma: methotrexate; hyper-CVAD - cyclophosphamide,vincristine, doxorubicin (also known as Adriamycin), and dexamethasone.Course B consists of methotrexate and cytarabine; CODOX-M –cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide,etoposide, and high-dose cytarabine; etoposide, vincristine,doxorubicin, cyclophosphamide, and prednisone (EPOCH) Lymphoplasmacyticlymphoma -rituximab

Hairy cell leukemia – cladribine (2-CdA) or pentostatin; rituximab;interferon-alfa

Current therapies for T-cell lymphomas include:

-   Precursor T-lymphoblastic lymphoma/leukemia - cyclophosphamide,    doxorubicin (Adriamycin), vincristine, L-asparaginase, methotrexate,    prednisone, and, sometimes, cytarabine (ara-C). Because of the risk    of spread to the brain and spinal cord, a chemo drug such as    methotrexate is also given into the spinal fluid. Skin lymphomas:    Gemcitabine Liposomal doxorubicin (Doxil); Methotrexate;    Chlorambucil; Cyclophosphamide; Pentostatin; Etoposide;    Temozolomide; Pralatrexate; R-CHOP-   Angioimmunoblastic T-cell lymphoma: prednisone or dexamethasone-   Extranodal natural killer/T-cell lymphoma, nasal type: CHOP-   Anaplastic large cell lymphoma: CHOP; pralatrexate (Folotyn),    targeted drugs such as bortezomib (Velcade) orromidepsin (Istodax),    or immunotherapy drugs such as alemtuzumab (Campath) and denileukin    diftitox (Ontak)-   Primary central nervous system (CNS) lymphoma - methotrexate;    rituximab

A more general list of suitable chemotherapeutic agents include, but arenot limited to, radioactive molecules, toxins, also referred to ascytotoxins or cytotoxic agents, which includes any agent that isdetrimental to the viability of cells, agents, and liposomes or othervesicles containing chemotherapeutic compounds. Examples of suitablechemotherapeutic agents include but are not limited to1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine,6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylatingagents, allopurinol sodium, altretamine, amifostine, anastrozole,anthramycin (AMC)), anti-mitotic agents, cis-dichlorodiamine platinum(II) (DDP) cisplatin), diamino dichloro platinum, anthracyclines,antibiotics, antis, asparaginase, BCG live (intravesical), betamethasonesodium phosphate and betamethasone acetate, bicalutamide, bleomycinsulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine,carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil,Cisplatin, Cladribine, Colchicin, conjugated estrogens,Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasinB, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerlyactinomycin), daunirubicin HCL, daunorucbicin citrate, denileukindiftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione,Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coliL-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterifiedestrogens, estradiol, estramustine phosphate sodium, ethidium bromide,ethinyl estradiol, etidronate, etoposide citrororum factor, etoposidephosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate,fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids,goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea,idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole,leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine,lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesteroneacetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna,methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane,mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL,paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL,plimycin, polifeprosan 20 with carmustine implant, porfimer sodium,procaine, procarbazine HCL, propranolol, rituximab, sargramostim,streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone,tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL,toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastinesulfate, vincristine sulfate, and vinorelbine tartrate.

Additional therapeutic agents that can be administered in combinationwith the compounds disclosed herein can include bevacizumab, sutinib,sorafenib, 2-methoxyestradiol, finasunate, vatalanib, vandetanib,aflibercept, volociximab, etaracizumab, cilengitide, erlotinib,cetuximab, panitumumab, gefitinib, trastuzumab, atacicept, rituximab,alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus,everolimus, lucatumumab, dacetuzumab, atiprimod, natalizumab,bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate,ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat,panobinostat, mapatumumab, lexatumumab, oblimersen, plitidepsin,talmapimod, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib,lenalidomide, thalidomide, simvastatin, and celecoxib.

In one aspect of the present invention, the compounds disclosed hereinare combined with at least one immunosuppressive agent. Theimmunosuppressive agent may be selected from the group consisting of acalcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.Cyclosporin A (NEORAL®), tacrolimus, a mTOR inhibitor, e.g. rapamycin ora derivative thereof, e.g. Sirolimus (RAPAMUNE®), Everolimus(Certican®), temsirolimus, biolimus-7, biolimus-9, a rapalog, e.g.azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod oran analogue thereof, an anti IL-8 antibody, mycophenolic acid or a saltthereof, e.g. sodium salt, or a prodrug thereof, e.g. MycophenolateMofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®,THYMOGLOBULIN®, Brequinar Sodium, 15-deoxyspergualin, tresperimus,Leflunomide ARAVA®, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®),Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone,pimecrolimus (Elidel®), abatacept, belatacept, etanercept (Enbrel®),adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody,natalizumab (Antegren®), Enlimomab, ABX-CBL, antithymocyteimmunoglobulin, siplizumab, and efalizumab.

Drugs sometimes used to treat autoimmune disorders include:methylprednisolone oral, Kenalog inj, Medrol oral, Medrol (Pak) oral,Depo-Medrol inj, prednisolone oral, Solu-Medrol inj, Solu-Medrol IV,Cortef oral, hydrocortisone oral, cortisone oral, Celestone Soluspaninj, Orapred oral, Orapred ODT oral, methylprednisolone acetate inj,betamethasone acet & sod phos inj, Veripred 20 oral, Solu-Medrol (PF)inj, methylprednisolone sodium succ IV, Solu-Medrol (PF) IV,methylprednisolone sodium succ inj, Solu-Cortef inj, Pediapred oral,Millipred oral, Aristospan Intra-Articular inj, hydrocortisone sodsuccinate inj, prednisolone sodium phosphate oral, methylprednisolonesod suc(PF) IV, Flo-Pred oral, triamcinolone hexacetonide inj,A-Hydrocort inj, A-Methapred inj, Millipred DP oral, prednisoloneacetate oral, Aristospan Intralesional inj, methylprednisolone sodsuc(PF) inj, hydrocortisone sod succ (PF) inj, Solu-Cortef (PF)injection and dexamethasone in 0.9 % NaCl IV.

Drug Conjugates

In one embodiment, the activity of an active compound for a purposedescribed herein can be augmented through conjugation to an agent thattargets the diseased or abnormally proliferating cell or otherwiseenhances activity, delivery, pharmacokinetics or other beneficialproperty.

For example, the compound can be administered as an antibody-drugconjugates (ADC). In certain embodiments, a selected compound describedherein can be administered in conjugation or combination with anantibody or antibody fragment. Fragments of an antibody can be producedthrough chemical or genetic mechanisms. In one embodiment, the antibodyfragment is an antigen binding fragment. For example, the antigenbinding fragment can be selected from an Fab, Fab′, (Fab′)2, or Fv. Inone embodiment, the antibody fragment is a Fab. Monovalent F(ab)fragments have one antigen binding site. In one embodiment, the antibodyis a divalent (Fab′)2 fragment, which has two antigen binding regionsthat are linked by disulfide bonds. In one embodiment, the antigenfragment is a (Fab′). Reduction of F(ab′)2 fragments produces twomonovalent Fab′ fragments, which have a free sulfhydryl group that isuseful for conjugation to other molecules.

In one embodiment, a selected compound described herein can beadministered in conjugation or combination with a Fv fragment. Fvfragments are the smallest fragment made from enzymatic cleavage of IgGand IgM class antibodies. Fv fragments have the antigen-binding sitemade of the VH and VC regions, but they lack the CH1 and CL regions. TheVH and VL chains are held together in Fv fragments by non-covalentinteractions.

In one embodiment, a selected compound as described herein can beadministered in combination with an antibody fragment selected from thegroup consisting of an ScFv, diabody, triabody, tetrabody, Bis-scFv,minibody, Fab2, or Fab3 antibody fragment. In one embodiment, theantibody fragment is a ScFv. Genetic engineering methods allow theproduction of single chain variable fragments (ScFv), which are Fv typefragments that include the VH and VL domains linked with a flexiblepeptide When the linker is at least 12 residues long, the ScFv fragmentsare primarily monomeric. Manipulation of the orientation of theV-domains and the linker length creates different forms of Fv moleculesLinkers that are 3-11 residues long yield scFv molecules that are unableto fold into a functional Fv domain. These molecules can associate witha second scFv molecule, to create a bivalent diabody. In one embodiment,the antibody fragment administered in combination with a selectedcompound described herein is a bivalent diabody. If the linker length isless than three residues, scFv molecules associate into triabodies ortetrabodies. In one embodiment, the antibody fragment is a triabody. Inone embodiment, the antibody fragment is a tetrabody. Multivalent scFvspossess greater functional binding affinity to their target antigensthan their monovalent counterparts by having binding to two more targetantigens, which reduces the off-rate of the antibody fragment. In oneembodiment, the antibody fragment is a minibody. Minibodies are scFv-CH3fusion proteins that assemble into bivalent dimers. In one embodiment,the antibody fragment is a Bis-scFv fragment. Bis-scFv fragments arebispecific. Miniaturized ScFv fragments can be generated that have twodifferent variable domains, allowing these Bis-scFv molecules toconcurrently bind to two different epitopes.

In one embodiment, a selected compound described herein is administeredin conjugation or combination with a bispecific dimer (Fab2) ortrispecific dimer (Fab3). Genetic methods are also used to createbispecific Fab dimers (Fab2) and trispecific Fab trimers (Fab3). Theseantibody fragments are able to bind 2 (Fab2) or 3 (Fab3) differentantigens at once.

In one embodiment, a selected compound described herein is administeredin conjugation or combination with an rIgG antibody fragment. rIgGantibody fragments refers to reduced IgG (75,000 daltons) or half-IgG.It is the product of selectively reducing just the hinge-regiondisulfide bonds. Although several disulfide bonds occur in IgG, those inthe hinge-region are most accessible and easiest to reduce, especiallywith mild reducing agents like 2-mercaptoethylamine (2-MEA). Half-IgGare frequently prepared for the purpose of targeting the exposinghinge-region sulfhydryl groups that can be targeted for conjugation,either antibody immobilization or enzyme labeling.

In other embodiments, a selected active compound described herein can belinked to a radioisotope to increase efficacy, using methods well knownin the art. Any radioisotope that is useful against the T, B or NKabnormal cells can be incorporated into the conjugate, for example, butnot limited to ¹³¹I, ¹²³I, ¹⁹²Ir, ³²P, ⁹⁰Sr, ¹⁹⁸Au, ²²⁶Ra, ⁹⁰Y, ²⁴¹Am,²⁵²Cf, ⁶⁰Co, or ¹³⁷Cs.

Of note, the linker chemistry can be important to efficacy andtolerability of the drug conjugates. The thio-ether linked T-DM1increases the serum stability relative to a disulfide linker version andappears to undergo endosomal degradation, resulting in intra-cellularrelease of the cytotoxic agent, thereby improving efficacy andtolerability, See, Barginear, M.F. and Budman, D.R., Trastuzumab-DM1: Areview of the novel immune-conjugate for HER2-overexpressing breastcancer, The Open Breast Cancer Journal, 1:25-30, 2009.

Examples of early and recent antibody-drug conjugates, discussing drugs,linker chemistries and classes of targets for product development thatmay be used in the present invention can be found in the reviews byCasi, G. and Neri, D., Antibody-drug conjugates: basic concepts,examples and future perspectives, J. Control Release 161(2):422-428,2012, Chari, R.V., Targeted cancer therapy: conferring specificity tocytotoxic drugs, Acc. Chem. Rev., 41(1):98-107, 2008, Sapra, P. andShor, B., Monoclonal antibody-based therapies in cancer: advances andchallenges, Pharmacol. Ther., 138(3):452-69, 2013, Schliemann, C. andNeri, D., Antibody-based targeting of the tumor vasculature, Biochim.Biophys. Acta., 1776(2):175-92, 2007, Sun, Y., Yu, F., and Sun, B.W.,Antibody-drug conjugates as targeted cancer therapeutics, Yao Xue XueBao, 44(9):943-52, 2009, Teicher, B.A., and Chari, R.V., Antibodyconjugate therapeutics: challenges and potential, Clin. Cancer Res.,17(20):6389-97,2011, Firer, M.A., and Gellerman, G.J., Targeted drugdelivery for cancer therapy: the other side of antibodies, J. Hematol.Oncol., 5:70, 2012, Vlachakis, D. and Kossida, S., Antibody DrugConjugate bioinformatics: drug delivery through the letterbox, Comput.Math. Methods Med., 2013; 2013:282398, Epub 2013 Jun 19, Lambert, J.M.,Drug-conjugated antibodies for the treatment of cancer, Br. J. Clin.Pharmacol., 76(2):248-62, 2013, Concalves, A., Tredan, O., Villanueva,C. and Dumontet, C., Antibody-drug conjugates in oncology: from theconcept to trastuzumab emtansine (T-DM1), Bull. Cancer,99(12):1183-1191, 2012, Newland, A.M., Brentuximab vedotin: aCD-30-directed antibody-cytotoxic drug conjugate, Pharmacotherapy,33(1):93-104, 2013, Lopus, M., Antibody-DM1 conjugates as cancertherapeutics, Cancer Lett., 307(2):113-118, 2011, Chu, Y.W. and Poison,A., Antibody-drug conjugates for the treatment of B-cell non-Hodgkin’slymphoma and leukemia, Future Oncol., 9(3):355-368, 2013, Bertholjotti,I., Antibody-drug conjugate - - a new age for personalized cancertreatment, Chimia, 65(9): 746-748, 2011, Vincent, K.J., and Zurini, M.,Current strategies in antibody engineering: Fc engineering and pH –dependent antigen binding, bispecific antibodies and antibody drugconjugates, Biotechnol. J., 7(12): 1444-1450, 2012, Haeuw, J.F.,Caussanel, V., and Beck, A., Immunoconjugates, drug-armed antibodies tofight against cancer, Med. Sci., 25(12): 1046-1052, 2009 and Govindan,S.V., and Goldenberg, D.M., Designing immunoconjugates for cancertherapy, Expert Opin. Biol. Ther., 12(7):873-890, 2012.

Pharmaceutical Compositions and Dosage Forms

The active compounds described herein, or their salt or prodrug can beadministered to the host using any suitable approach which achieves thedesired therapeutic result. The amount and timing of active compoundadministered will, of course, be dependent on the host being treated,the instructions of the supervising medical specialist, on the timecourse of the exposure, on the manner of administration, on thepharmacokinetic properties of the particular active compound, and on thejudgment of the prescribing physician. Thus, because of host to hostvariability, the dosages given below are a guideline and the physiciancan titrate doses of the compound to achieve the treatment that thephysician considers appropriate for the host. In considering the degreeof treatment desired, the physician can balance a variety of factorssuch as age and weight of the host, presence of preexisting disease, aswell as presence of other diseases. Pharmaceutical formulations can beprepared for any desired route of administration including, but notlimited to, systemic, topical, oral, intravenous, subcutaneous,transdermal, buccal, sublingual, intraaortal, intranasal, parenteral, oraerosol administration, as discussed in greater detail below.

The therapeutically effective dosage of any active compound describedherein will be determined by the health care practitioner depending onthe condition, size and age of the patient as well as the route ofdelivery. In one non-limited embodiment, a dosage from about 0.1 toabout 200 mg/kg has therapeutic efficacy, with all weights beingcalculated based upon the weight of the active compound, including thecases where a salt is employed. In some embodiments, the dosage can bethe amount of compound needed to provide a serum concentration of theactive compound of up to between about 1 and 5, 10, 20, 30, or 40 µM. Insome embodiments, a dosage from about 10 mg/kg to about 50 mg/kg can beemployed for oral administration. Typically, a dosage from about 0.5mg/kg to 5 mg/kg can be employed for intramuscular injection. In someembodiments, dosages can be from about 1 µmol/kg to about 50 µmol/kg,or, optionally, between about 22 µmol/kg and about 33 µmol/kg of thecompound for intravenous or oral administration. An oral dosage form caninclude any appropriate amount of active material, including for examplefrom 5 mg to, 50, 100, 200, or 500 mg per tablet or other solid dosageform.

In accordance with certain embodiments of the invention, in thepresently disclosed methods, pharmaceutically active compounds asdescribed herein can be administered orally as a solid or as a liquid,or can be administered intramuscularly, intravenously, or by inhalationas a solution, suspension, or emulsion. In some embodiments, thecompounds or salts also can be administered by inhalation,intravenously, or intramuscularly as a liposomal suspension. Whenadministered through inhalation the active compound or salt can be inthe form of a plurality of solid particles or droplets having anydesired particle size, and for example, from about 0.01, 0.1 or 0.5 toabout 5, 10, 20 or more microns, and optionally from about 1 to about 2microns. Compounds as disclosed in the present invention havedemonstrated good pharmacokinetic and pharmacodynamics properties, forinstance when administered by the oral or intravenous routes.

The pharmaceutical formulations can comprise an active compounddescribed herein or a pharmaceutically acceptable salt thereof, in anypharmaceutically acceptable carrier. If a solution is desired, water maybe the carrier of choice for water-soluble compounds or salts. Withrespect to the water-soluble compounds or salts, an organic vehicle,such as glycerol, propylene glycol, polyethylene glycol, or mixturesthereof, can be suitable. In the latter instance, the organic vehiclecan contain a substantial amount of water. The solution in eitherinstance can then be sterilized in a suitable manner known to those inthe art, and for illustration by filtration through a 0.22-micronfilter. Subsequent to sterilization, the solution can be dispensed intoappropriate receptacles, such as depyrogenated glass vials. Thedispensing is optionally done by an aseptic method. Sterilized closurescan then be placed on the vials and, if desired, the vial contents canbe lyophilized.

In addition to the active compounds or their salts, the pharmaceuticalformulations can contain other additives, such as pH-adjustingadditives. In particular, useful pH-adjusting agents include acids, suchas hydrochloric acid, bases or buffers, such as sodium lactate, sodiumacetate, sodium phosphate, sodium citrate, sodium borate, or sodiumgluconate. Further, the formulations can contain antimicrobialpreservatives. Useful antimicrobial preservatives include methylparaben,propylparaben, and benzyl alcohol. An antimicrobial preservative istypically employed when the formulations is placed in a vial designedfor multi-dose use. The pharmaceutical formulations described herein canbe lyophilized using techniques well known in the art.

For oral administration a pharmaceutical composition can take the formof solutions, suspensions, tablets, pills, capsules, powders, and thelike. Tablets containing various excipients such as sodium citrate,calcium carbonate and calcium phosphate may be employed along withvarious disintegrants such as starch (e.g., potato or tapioca starch)and certain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate,and talc are often very useful for tableting purposes. Solidcompositions of a similar type may be employed as fillers in soft andhard-filled gelatin capsules. Materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the compounds of the presently disclosed host matter canbe combined with various sweetening agents, flavoring agents, coloringagents, emulsifying agents and/or suspending agents, as well as suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

In yet another embodiment of the host matter described herein, there areprovided injectable, stable, sterile formulations comprising an activecompound as described herein, or a salt thereof, in a unit dosage formin a sealed container. The compound or salt is provided in the form of alyophilizate, which is capable of being reconstituted with a suitablepharmaceutically acceptable carrier to form liquid formulation suitablefor injection thereof into a host. When the compound or salt issubstantially water-insoluble, a sufficient amount of emulsifying agent,which is physiologically acceptable, can be employed in sufficientquantity to emulsify the compound or salt in an aqueous carrier.Particularly useful emulsifying agents include phosphatidyl cholines andlecithin.

Additional embodiments provided herein include liposomal formulations ofthe active compounds disclosed herein. The technology for formingliposomal suspensions is well known in the art. When the compound is anaqueous-soluble salt, using conventional liposome technology, the samecan be incorporated into lipid vesicles. In such an instance, due to thewater solubility of the active compound, the active compound can besubstantially entrained within the hydrophilic center or core of theliposomes. The lipid layer employed can be of any conventionalcomposition and can either contain cholesterol or can becholesterol-free. When the active compound of interest iswater-insoluble, again employing conventional liposome formationtechnology, the salt can be substantially entrained within thehydrophobic lipid bilayer that forms the structure of the liposome. Ineither instance, the liposomes that are produced can be reduced in size,as through the use of standard sonication and homogenization techniques.The liposomal formulations comprising the active compounds disclosedherein can be lyophilized to produce a lyophilizate, which can bereconstituted with a pharmaceutically acceptable carrier, such as water,to regenerate a liposomal suspension.

Pharmaceutical formulations also are provided which are suitable foradministration as an aerosol by inhalation. These formulations comprisea solution or suspension of a desired compound described herein or asalt thereof, or a plurality of solid particles of the compound or salt.The desired formulations can be placed in a small chamber and nebulized.Nebulization can be accomplished by compressed air or by ultrasonicenergy to form a plurality of liquid droplets or solid particlescomprising the compounds or salts. The liquid droplets or solidparticles may for example have a particle size in the range of about 0.5to about 10 microns, and optionally from about 0.5 to about 5 microns.The solid particles can be obtained by processing the solid compound ora salt thereof, in any appropriate manner known in the art, such as bymicronization. Optionally, the size of the solid particles or dropletscan be from about 1 to about 2 microns. In this respect, commercialnebulizers are available to achieve this purpose. The compounds can beadministered via an aerosol suspension of respirable particles in amanner set forth in U.S. Pat. No. 5,628,984, the disclosure of which isincorporated herein by reference in its entirety.

When the pharmaceutical formulations suitable for administration as anaerosol is in the form of a liquid, the formulations can comprise awater-soluble active compound in a carrier that comprises water. Asurfactant can be present, which lowers the surface tension of theformulations sufficiently to result in the formation of droplets withinthe desired size range when hosted to nebulization.

The term “pharmaceutically acceptable salts” as used herein refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with hosts (e.g., human hosts) without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe presently disclosed host matter.

Thus, the term “salts” refers to inorganic and organic acid additionsalts of compounds of the presently disclosed compounds. These salts canbe prepared by any means known in the art, including, withoutlimitation, in situ during the final isolation and purification of thecompounds or by separately reacting the purified compound in its freebase form with a suitable organic or inorganic acid and isolating thesalt thus formed. As the compounds of the presently disclosed hostmatter are basic compounds, they are all capable of forming a widevariety of different salts with various inorganic and organic acids.Acid addition salts of the basic compounds are prepared by contactingthe free base form with a sufficient amount of the desired acid toproduce the salt in the conventional manner. The free base form can beregenerated by contacting the salt form with a base and isolating thefree base in the conventional manner. The free base forms may differfrom their respective salt forms in certain physical properties such assolubility in polar solvents. Pharmaceutically acceptable base additionsalts may be formed with metals or amines, such as alkali and alkalineearth metal hydroxides, or of organic amines. Examples of metals used ascations, include, but are not limited to, sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines include, but are notlimited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methylglucamine, and procaine.Thebase addition salts of acidic compounds are prepared by contacting thefree acid form with a sufficient amount of the desired base to producethe salt in the conventional manner. The free acid form can beregenerated by contacting the salt form with an acid and isolating thefree acid in a conventional manner. The free acid forms may differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents.

Salts can be prepared from inorganic acids sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric,phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate,glucoheptonate, lactobionate, laurylsulphonate and isethionate salts,and the like. Salts can also be prepared from organic acids, such asaliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoicacids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids,aliphatic and aromatic sulfonic acids, etc. and the like. Representativesalts include acetate, propionate, caprylate, isobutyrate, oxalate,malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Pharmaceuticallyacceptable salts can include cations based on the alkali and alkalineearth metals, such as sodium, lithium, potassium, calcium, magnesium andthe like, as well as non-toxic ammonium, quaternary ammonium, and aminecations including, but not limited to, ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine, and the like. Also contemplated are the saltsof amino acids such as arginate, gluconate, galacturonate, and the like.See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which isincorporated herein by reference.

Syntheses

The disclosed compounds can be made by the following general schemes:

In Scheme 1, Ref-1 is WO 2010/020675 A1; Ref-2 is White, J. D.; et al.J. Org. Chem. 1995, 60, 3600; and Ref-3 Presser, A. and Hufner, A.Monatshefte für Chemie 2004, 135, 1015.

In Scheme 2, Ref-1 is WO 2010/020675 A1; Ref-4 is WO 2005/040166 A1; andRef-5 is Schoenauer, K and Zbiral, E. Tetrahedron Letters 1983, 24, 573.

In Scheme 3, Ref ― 1 is WO 2010/020675 A1.

In Scheme 8, Ref-1 is WO 2010/020675 A1; Ref-2 is WO 2005/040166 A1; andRef-3 is Schoenauer, K and Zbiral, E. Tetrahedron Letters 1983, 24, 573.

Alternatively, the lactam can be generated by reacting the carboxylicacid with a protected amine in the presence of a strong acid and adehydrating agent, which can be together in one moiety as a strong acidanhydride. Examples of strong acid anhydrides include, but are notlimited to, trifluoroacetic acid anhydride, tribromoacetic acidanhydride, trichloroacetic acid anhydride, or mixed anhydrides. Thedehydrating agent can be a carbodiimide based compound such as but notlimited to DCC (N,N-dicyclohexylcarbodiimide), EDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or DIC(N,N-diisopropylcarbodiimide). An additional step may be necessary totake off the N-protecting group and the methodologies are known to thoseskilled in the art.

Other amine intermediates and final amine compounds can be synthesizedby those skilled in the art. It will be appreciated that the chemistrycan employ reagents that comprise reactive functionalities that can beprotected and de-protected and will be known to those skilled in the artat the time of the invention. See for example, Greene, T.W. and Wuts,P.G.M., Greene’s Protective Groups in Organic Synthesis, 4^(th) edition,John Wiley and Sons.

EXAMPLES

Intermediates B, E, K, L, 1A, 1E and 1CA were prepared according to themethods of Tavares, F.X. and Strum, J.C., See, US 8598,186 entitled CDKinhibitors.

Pats. US 8598186 entitled CDK Inhibitors to Tavares, F.X. and Strum,J.C., WO 2013/163239 entitled Synthesis of Lactams to Tavares, F.X., andWO 2013/148748 entitled Lactam Kinase Inhibitors to Tavares, F.X. areherein incorporated by reference in their entirety.

Example 1 Synthesis of Tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4yl)amino]ethyl]carbamate, Compound 1

To a solution of 5-bromo-2,4-dichloropyrimidine (3.2 g, 0.0135 mol) inethanol (80 mL) was added Hunig’s base (3.0 mL) followed by the additionof a solution of N-(tert-butoxycarbonyl)-1,2-diaminoethane (2.5 g,0.0156 mole) in ethanol (20 mL). The contents were stirred overnight for20 hrs. The solvent was evaporated under vacuum. Ethyl acetate (200 mL)and water (100 mL) were added and the layers separated. The organiclayer was dried with magnesium sulfate and then concentrated undervacuum. Column chromatography on silica gel using hexane/ethyl acetate(0- 60%) afforded tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. ¹HNMR(d6-DMSO) δ ppm 8.21 (s, 1H), 7.62 (brs, 1H), 7.27 (brs, 1H), 3.39 (m,2H), 3.12 (m, 2H), 1.34 (s, 9H). LCMS (ESI) 351 (M + H).

Example 2 Synthesis of Tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate,Compound 2

To tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (1.265 g,3.6 mmol) in THF (10 mL) was added the acetal (0.778 mL, 5.43 mmol),Pd(dppf)CH₂Cl₂ (148 mg), and triethylamine (0.757 mL, 5.43 mmol). Thecontents were degassed and then purged with nitrogen. To this was thenadded CuI (29 mg). The reaction mixture was heated at reflux for 48 hrs.After cooling, the contents were filtered over CELITE™ and concentrated.Column chromatography of the resulting residue using hexane/ethylacetate (0- 30%) afforded tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate.¹HNMR (d6-DMSO) δ ppm 8.18 (s, 1H), 7.63 (brs, 1H), 7.40 (brs, 1H), 5.55(s, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 3.15 (m, 2H), 1.19 -1.16 (m, 15H). LCMS (ESI) 399 (M + H).

Example 3 Synthesis of Tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate,Compound 3

To a solution of the coupled product (2.1 g, 0.00526 mole) in THF (30mL) was added TBAF solid (7.0 g). The contents were heated to andmaintained at 65 degrees for 2 hrs. Concentration followed by columnchromatography using ethyl acetate/hexane (0-50%) afforded tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamateas a pale brown liquid (1.1 g). ¹HNMR (d6-DMSO) δ ppm 8.88 (s, 1H), 6.95(brs, 1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29 (m, 2H), 3.59 (m, 4H), 3.34(m, 1H), 3.18 (m, 1H), 1.19 (m, 9H), 1.17 (m, 6H). LCMS (ESI) 399 (M +H).

Example 4 Synthesis of Tert-butylN-[2-(2-chloro-6-formyl-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]carbamate,Compound 4

To the acetal (900 mg) from the preceeding step was added AcOH (8.0 mL)and water (1.0 mL). The reaction was stirred at room temperature for 16hrs. Conc. and column chromatography over silica gel using ethylacetate/hexanes (0- 60%) afforded tert-butylN-[2-(2-chloro-6-formyl-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]carbamate asa foam (0.510 g). ¹HNMR (d6-DMSO) δ ppm 9.98 (s, 1H), 9.18 (s, 1H), 7.66(s, 1H), 6.80 (brs, 1H), 4.52 (m, 2H), 4.36 (m, 2H), 1.14 (s, 9H). LCMS(ESI) 325 (M + H).

Example 5 Synthesis of7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid, Compound 5

To the aldehyde (0.940 g) from the preceeding step in DMF (4 mL) wasadded oxone (1.95 g, 1.1 eq). The contents were stirred at room temp for7 hrs. Silica gel column chromatography using hexane/ethyl acetate (0-100%) afforded7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid (0.545 g). ¹HNMR (d6-DMSO) δ ppm 9.11 (s, 1H), 7.39 (s, 1H), 4.38(m, 2H), 4.15 (m, 2H), 1.48 (m, 9H). LCMS (ESI) 341(M + H).

Example 6 Synthesis of Methyl7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylate,Compound 6

To a solution of 2-chloro-7-propyl-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid (0.545 g, 0.00156 mole) from the preceeding step in toluene (3.5mL) and MeOH (1 mL) was added TMS-diazomethane (1.2 mL). After stirringovernight at room temperature, the excess of TMS-diazomethane wasquenched with acetic acid (3 mL) and the reaction was concentrated undervacuum. The residue was purified by silica gel column chromatographywith hexane/ethyl acetate (0- 70%) to afford methyl7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylateas an off white solid (0.52 g). ¹HNMR (d6-DMSO) δ ppm 9.10 (s, 1H), 7.45(s, 1H), 6.81 (brs, 1H) 4.60 (m, 2H), 3.91 (s, 3H), 3.29 (m, 2H), 1.18(m, 9H) LCMS (ESI) 355 (M + H).

Example 7 Synthesis of Chloro Tricyclic Amide, Compound 7

To methyl7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylate(0.50 g, 0.0014 mole) from the preceeding step in dichloromethane (2.0mL) was added TFA (0.830 mL). The contents were stirred at roomtemperature for 1 hr. Concentration under vacuum afforded the crudeamino ester which was suspended in toluene (5 mL) and Hunig’s base (0.5mL). The contents were heated at reflux for 2 hrs. Concentrationfollowed by silica gel column chromatography using hexane/ethyl acetate(0- 50%) afforded the desired chloro tricyclic amide (0.260 g). ¹HNMR(d6-DMSO) δ ppm 9.08 (s, 1H), 8.48 (brs, 1H), 7.21 (s, 1H) 4.33 (m, 2H),3.64 (m, 2H). LCMS (ESI) 223 (M + H).

Example 8 Synthesis of Chloro-N-Methyltricyclic Amide, Compound 8

To a solution of the chloro tricycliclactam, Compound 7, (185 mg,0.00083 mole) in DMF (2.0 mL) was added sodium hydride (55% dispersionin oil, 52 mg). After stirring for 15 mins, methyl iodide (62 µL, 1.2eq). The contents were stirred at room temperature for 30 mins. Afterthe addition of methanol (5 mL), sat NaHCO₃ was added followed by theaddition of ethyl acetate. Separation of the organic layer followed bydrying with magnesium sulfate and concentration under vacuum affordedthe N-methylated amide in quantitative yield. ¹HNMR (d6-DMSO) δ ppm 9.05(s, 1H), 7.17 (s, 1H) 4.38 (m, 2H), 3.80 (m, 2H), 3.05 (s, 3H). LCMS(ESI) 237 (M + H).

Example 9 Synthesis of 1-methyl-4-(6-nitro-3-pyridyl)piperazine,Compound 9

To 5-bromo-2-nitropyridine (4.93 g, 24.3 mmole) in DMF (20 mL) was addedN-methylpiperazine (2.96 g, 1.1 eq) followed by the addition of DIPEA(4.65 mL, 26.7 mmole). The contents were heated at 90 degrees for 24hrs. After addition of ethyl acetate (200 mL), water (100 mL) was addedand the layers separated. Drying followed by concentration afforded thecrude product which was purified by silica gel column chromatographyusing (0-10%) DCM/Methanol. ¹HNMR (d6-DMSO) δ ppm 8.26 (s, 1H), 8.15(1H, d, J = 9.3 Hz), 7.49 (1H, d, J = 9.4 Hz), 3.50 (m, 4H), 2.49 (m,4H), 2.22 (s, 3H).

Example 10 Synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine,Compound 10

To 1-methyl-4-(6-nitro-3-pyridyl)piperazine (3.4 g) in ethyl acetate(100 mL) and ethanol (100 mL) was added 10% Pd/C (400 mg) and then thereaction was stirred under hydrogen (10 psi) overnight. After filtrationthrough CELITE™, the solvents were evaporated and the crude product waspurified by silica gel column chromatography using DCM/ 7N ammonia inMeOH (0- 5%) to afford 5-(4-methylpiperazin-1-yl)pyridin-2-amine (2.2g). ¹HNMR (d6-DMSO) δ ppm 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36(1H, d, J = 8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16(s, 3H).

Example 11 Synthesis of Tert-butyl4-(6-amino-3-pyridyl)piperazine-1-carboxylate, Compund 11

This compound was prepared as described in WO 2010/020675 A1.

Example 12 Synthesis of Tert-ButylN-[2-(benzyloxycarbonylamino)-3-methyl-butyl] Carbamate, Compound 12

To benzyl N-[1-(hydroxymethyl)-2-methyl-propyl]carbamate (11.0 g, 0.0464mole) in dioxane (100 mL) cooled to 0° C. was added diphenylphosphorylazide (10.99 mL, 1.1 eq) followed by the addition of DBU (8.32 mL, 1.2eq). The contents were allowed to warm to room temperature and stirredfor 16 hrs. After the addition of ethyl acetate (300 mL) and water (100mL), the organic layer was separated and washed with satd. NaHCO₃ (100mL). The organic layer was then dried (magnesium sulfate) andconcentrated under vacuum. To this intermediate in DMSO (100 mL) wasadded sodium azide (7.54 g) and the contents then heated to 90 degreesfor 2 hrs. After addition of ethyl acetate and water the layers wereseparated. The organic layer was dried with magnesium sulfate followedby concentration under vacuum to afford an oil that was purified bysilica gel column chromatography using hexane/ethyl acetate (0- 70%) toafford benzyl N-[1-(azidomethyl)-2-methyl-propyl] carbamate 6.9 g as acolorless oil.

To benzyl N-[1-(azidomethyl)-2-methyl-propyl] carbamate (6.9 g, 0.0263mole) in THF (100 mL) was added triphenyl phosphine (7.59 g, 1.1 eq).The contents were stirred for 20 hrs. After addition of water (10 mL),and stirring for an additional 6 hrs, ethyl acetate was added and thelayers separated. After drying with magnesium sulfate and concentrationunder vacuum, the crude product was purified by silica gel columnchromatography using DCM/MeOH (0 - 10%) to afford benzylN-[1-(aminomethyl)-2-methyl-propyl] carbamate as a yellow oil.

To benzyl N-[1-(aminomethyl)-2-methyl-propyl] carbamate (4.65 g, 0.019mole) in THF (70 mL) was added 2 N NaOH (20 mL) followed by the additionof di-tert-butyl dicarbonate (5.15 g, 1.2 eq). After stirring for 16hrs, ethyl acetate was added and the layers separated. After drying withmagnesium sulfate and concentration under vacuum, the crude product waspurified using hexane/ethyl acetate (0- 40%) over a silica gel column toafford intermediate A, tert-butylN-[2-(benzyloxycarbonylamino)-3-methyl-butyl] carbamate, (6.1 g). ¹HNMR(600 MHz, CHLOROFORM-d) δ ppm 0.89 (d, J=6.73 Hz, 3 H) 0.92 (d, J=6.73Hz, 3 H) 1.38 (s, 9 H) 1.70 -1.81 (m, 1 H) 3.18 (d, J=5.56 Hz, 2 H)3.47 - 3.60 (m, 1 H) 4.76 (s, 1 H) 4.89 (d, J=7.90 Hz, 1 H) 5.07 (s, 2H) 7.25 - 7.36 (m, 5 H). LCMS (ESI) 337 (M + H).

Example 13 Synthesis of Tert-butylN-[2-(benzyloxycarbonylamino)-4-methyl-pentyl] Carbamate, Compound 13

To a solution of benzyl N-[1-(hydroxymethyl)-3-methyl-butyl]carbamate(6.3 g, 0.025 mole) in DCM (100 mL) was added diisopropylethyl amine(5.25 mL, 1.2 eq) followed by the addition of methane sulfonylchloride(2.13 mL, 1.1 eq) at 0 degrees. After stirring for 3 hrs, water (100 mL)was added and the organic layer separated. After drying with magnesiumsulfate and concentration under vacuum, the crude[2-(benzyloxycarbonylamino)-4-methyl-pentyl] methanesulfonate which wastaken directly to the next step.

To the crude [2-(benzyloxycarbonylamino)-4-methyl-pentyl]methanesulfonate from the above reaction in DMF (50 mL), was addedsodium azide 2.43 g. The reaction mixture was then heated to 85 degreesfor 3 hrs. After cooling, ethyl acetate (300 mL) and water was added.The organic layer was separated, dried with magnesium sulfate and thenconcentrated under vacuum to afford the crude benzylN-[1-(azidomethyl)-3-methyl-butyl] carbamate. To this crude intermediatewas added THF (100 mL) followed by triphenylphosphine 7.21 g and stirredunder nitrogen for 16 hrs. After addition of water (10 mL), and stirringfor an additional 6 hrs, ethyl acetate was added and the layersseparated. After drying with magnesium sulfate and concentration undervacuum, the crude product was columned using DCM/MeOH (0 - 10%) toafford benzyl N-[1-(aminomethyl)-3-methyl-butyl] carbamate (4.5 g).

To benzyl N-[1-(aminomethyl)-3-methyl-butyl] carbamate (4.5 g, 0.018mole) in THF (60 mL) was added 2N NaOH (18 mL) followed by the additionof di-tert-butyl dicarbonate (4.19 g, 1.07 eq). After stirring for 16hrs, ethyl acetate was added and the layers separated. After drying withmagnesium sulfate and concentration under vacuum, the crude product wastaken to the next step. ¹HNMR (600 MHz, CHLOROFORM-d) δ ppm 0.89 (d,J=6.73 Hz, 6 H) 1.25 - 1.34 (m, 1 H) 1.39 (s, 9 H) 1.57 - 1.71 (m, 2 H)3.04 - 3.26 (m, 2 H) 3.68 - 3.80 (m, 1 H) 4.72 - 4.89 (m, 2 H) 5.06 (s,2 H) 7.25 - 7.38 (m, 5 H). LCMS (ESI) 351 (M + H).

Example 14 Synthesis of Tert-butylN-[(2R)-2-(benzyloxycarbonylamino)-3-methyl-butyl] Carbamate, Compound14

Compound 14 was synthesized from benzylN-[(1R)-1-(hydroxymethyl)-2-methyl-propyl] carbamate using similarsynthetic steps as that described for Compound 13. The analytical data(NMR and mass spec) was consistent with that for Compound 12.

Example 15 Synthesis of Tert-butylN-[(2S)-2-(benzyloxycarbonylamino)-3-methyl-butyl]carbamate, Compund 15

Compound 15 was synthesized from benzylN-[(1S)-1-(hydroxymethyl)-2-methyl-propyl] carbamate using similarsynthetic steps as that described for Compound 13. The analytical data(NMR and mass spec) was consistent with that for Compound 12.

Example 16 Synthesis of Tert-butylN-[(1S)-1-(aminomethyl)-2-methyl-propyl]carbamate, Compound 16

To a solution of tert-butylN-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]carbamate carbamate (6.3 g,0.025 mole) in THF (100 mL) was added diisopropylethyl amine (5.25 mL,1.2 eq) followed by the addition of methane sulfonylchloride (2.13 mL,1.1 eq) at 0 degrees. After stirring for 3 hrs, water (100 mL) was addedand the organic layer separated. After drying with magnesium sulfate andconcentration under vacuum, the crude[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butyl] methanesulfonate wastaken directly to the next step.

To the crude [(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butyl]methanesulfonate from the above reaction in DMSO (50 mL), was addedsodium azide (2.43 g). The reaction mixture was then heated to 85degrees for 3 hrs. After cooling, ethyl acetate (300 mL) and water wereadded. The organic layer was separated, dried with magnesium sulfate andthen concentrated under vacuum to afford the crude benzylN-[1-(azidomethyl)-3-methyl-butyl] carbamate. To this crude intermediatewas added THF (100 mL) followed by triphenylphosphine (7.21 g) and thereation was stirred under nitrogen for 16 hrs. After addition of water(10 mL), and stirring for an additional 6 hrs, ethyl acetate was addedand the layers separated. After drying with magnesium sulfate andconcentration under vacuum, the crude product was purified by silica gelcolumn chromatography using DCM/MeOH (0 - 10%) to afford benzylN-[1-(aminomethyl)-3-methylbutyl] carbamate (4.5 g). LCMS (ESI) 203 (M +H).

Example 17 Synthesis of Tert-butylN-[(1R)-1-(aminomethyl)-2-methyl-propyl]carbamate, Compound 17

Compound 17 was synthesized from tert-butylN-[(1R)-1-(hydroxymethyl)-2-methylpropyl] carbamate using a similarsynthetic sequence as described for Compound 16. The analytical data(NMR and mass spec) was consistent with Compound 16.

Example 18 Synthesis of Tert-butylN-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentyl] Carbamate, Compound18

Compound 18 was synthesized from benzylN-[(1S)-1-(hydroxymethyl)-3-methylbutyl]carbamate using a similarsynthetic sequence as described for Compound 13. The analytical data(NMR and mass spec) was consistent with Compound 13.

Example 19 Synthesis of Tert-butylN-[(2S)-2-(benzyloxycarbonylamino)-2-phenyl-ethyl] Carbamate, Compound19

Compound 19 was synthesized from benzylN-[(1S)-2-hydroxy-1-phenyl-ethyl] carbamate using a similar syntheticsequence as described for Compound 13. ¹HNMR (600 MHz, DMSO-d₆) δ ppm1.20 - 1.33 (m, 9 H) 3.11 (t, J=6.29 Hz, 2 H) 4.59 - 4.68 (m, 1 H)4.88 - 5.01 (m, 2 H) 6.81 (t, J=5.42 Hz, 1 H) 7.14 - 7.35 (m, 10 H) 7.69(d, J=8.49 Hz, 1 H). LCMS (ESI) 371 (M + H).

Example 20 Synthesis of Tert-butylN-[(2S)-2-(benzyloxycarbonylamino)-3-methyl-pentyl] Carbamate, Compound20

Compound 20 was synthesized from benzylN-[(1S)-1-(hydroxymethyl)-2-methyl-butyl] carbamate using a similarsynthetic sequence as described for Compound 13. ¹HNMR (600 MHz,CHLOROFORM-d) δ ppm 0.85 - 0.92 (m, 6 H) 1.05 - 1.15 (m, 1 H) 1.35 -1.41 (m, 9 H) 1.45 -1.56 (m, 2 H) 3.14 - 3.24 (m, 2 H) 3.54 - 3.64 (m, 1H) 4.78 (s, 1 H) 4.96 (d, J=7.91 Hz, 1 H) 5.06 (s, 2 H) 7.27 - 7.37 (m,5 H). LCMS (ESI) 351 (M + H).

Example 21 Synthesis of Tert-butylN-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butyl] Carbamate,Compound 21

Compound 21 was synthesized from benzylN-[(1S)-1-(hydroxymethyl)-2,2-dimethyl-propyl]carbamate using a similarsynthetic sequence as described for Compound 13. LCMS (ESI) 351.

Example 22 Synthesis of Tert-butylN-[[1-(benzyloxycarbonylamino)cyclohexyl]methyl] Carbamate, Compound 22

To a solution of benzyl N-[1-(aminomethyl)cyclohexyl]carbamate (10.0 g,0.0381 mole) in THF (150 mL) was added di-tert-butyl dicarbonate (9.15g, 1.1 eq) and the contents were stirred at room temperature for 16 hrs.Ethyl acetate and water were then added. The organic layer wasseparated, dried over magnesium sulfate and then concentrated undervacuum to afford tert-butylN-[[1-(benzyloxycarbonylamino)cyclohexyl]methyl] carbamate (13.1 g).¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.92 - 1.54 (m, 17 H) 1.76 - 2.06 (m, 2H) 3.09 (d, J=6.15 Hz, 2 H) 4.92 (s, 2 H) 6.63 (d, J=17.27 Hz, 1 H)7.16 - 7.49 (m, 6 H). LCMS (ESI) 363 (M + H).

Example 23 Synthesis of Tert-butylN-[[1-(benzyloxycarbonylamino)cyclopentyl]methyl] Carbamate, Compound 23

tert-butyl N-[[1-(benzyloxycarbonylamino)cyclopentyl]methyl]carbamatewas synthesized in an analogous manner to tert-butylN-[[1-(benzyloxycarbonylamino) cyclohexyl]methyl] carbamate. LCMS (ESI)349 (M + H).

Example 24 Synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine,Compound 24

To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL) was added1-(4-piperidyl)piperidine (1.0 g, 5.9 mmole) and triethylamine (0.99 mL,7.1 mmole). The contents were heated to 120° C. in a CEM Discoverymicrowave system for 3 hours. The crude reaction was then purified bysilica gel column chromatography with DCM/methanol (0-20%) to afford2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine as an oil (457 mg).¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76(m, 2 H) 2.37 (m, 5 H) 2.94 (t, J=12.74 Hz, 2 H) 4.06 (d, J=13.47 Hz, 2H) 7.41 (dd, J=9.37, 2.64 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1 H) 8.20 (d,J=2.64 Hz, 1 H).

Example 25 Synthesis of 5-[4-(1-piperidyl)-1-piperidyl]pyridin-2-amine,Compound 25

5-(1-piperidyl)-1-piperidyl]pyridin-2-amine was prepared in a mannersimilar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine. ¹HNMR (600 MHz, DMSO-d₆) δppm 1.13 - 1.37 (m, 6 H) 1.40 - 1.63 (m, 6 H) 1.71 (m, 2 H), 2.24 (m,1H) 2.43 (m, 2 H) 3.33 (d, J=12.30 Hz, 2 H) 5.31 (s, 2 H) 6.33 (d,J=8.78 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.64 Hz, 1H). LCMS (ESI) 261 (M + H).

Example 26 Synthesis of 4-[1-(6-nitro-3-pyridyl)-4-piperidyl]Morpholine, Compound 26

4-(6-nitro-3-pyridyl)-4-piperidyl]morpholine was synthesized in a mannersimilar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.41 (m, 2 H) 1.82 (m, 2 H) 2.42 (m, 5 H) 2.98 (t,J=12.44 Hz, 2 H) 3.52 (s, 4 H) 4.04 (d, J=12.88 Hz, 2 H) 7.42 (d, J=9.37Hz, 1 H) 8.08 (d, J=9.08 Hz, 1 H) 8.21 (s, 1 H).

Example 27 Synthesis of 5-(4-morpholino-1-piperidyl) Pyridin-2-amine,Compound 27

5-morpholino-1-piperidyl)pyridin-2-amine was prepared in a mannersimilar to that used in the synthesis of5-methylpiperazin-1-yl)pyridin-2-amine. ¹HNMR (600 MHz, DMSO-d₆) δ ppm1.34 - 1.52 (m, 2 H) 1.78 (m, 2 H) 2.14 (m, 1 H) 2.43 (m, 4 H) 3.32 (d,J=12.30 Hz, 4 H) 3.47 - 3.59 (m, 4 H) 5.32 (s, 2 H) 6.34 (d, J=8.78 Hz,1 H) 7.11 (dd, J=8.93, 2.78 Hz, 1 H) 7.47 - 7.62 (m, 1 H). LCMS (ESI)263 (M + H).

Example 28 Synthesis of 4-[1-(6-nitro-3-pyridyl)-4-piperidyl]Thiomorpholine, Compound 28

4-(6-nitro-3-pyridyl)-4-piperidyl] thiomorpholine was synthesized in amanner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.40 - 1.52 (m, 2H) 1.71 (m, 2 H) 2.49 - 2.55 (m, 4 H)2.56 - 2.63 (m, 1 H) 2.68 - 2.75 (m, 4 H) 2.88 - 2.98 (m, 2 H) 4.09 (d,J=13.18 Hz, 2 H) 7.42 (dd, J=9.22, 3.07 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1H) 8.20 (d, J=3.22 Hz, 1 H).

Example 29 Synthesis of 5-(4-thiomorpholino-1-piperidyl)Pyridin-2-amine, Compound 29

5-thiomorpholino-1-piperidyl) pyridin-2-amine was prepared in a mannersimilar to that used in the synthesis of5-methylpiperazin-1-yl)pyridin-2-amine. ¹HNMR (600 MHz, DMSO-d₆) δ ppm1.47 - 1.59 (m, 2 H) 1.65 (m, 2 H) 2.22 - 2.38 (m, 1 H) 2.50 - 2.59 (m,6 H) 2.68 - 2.82 (m, 4 H) 3.33 (d, J=12.00 Hz, 2 H) 5.31 (s, 2 H) 6.33(d, J=9.08 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.64 Hz,1 H). LCMS (ESI) 279 (M + H).

Example 30 Synthesis of 2-nitro-5-(1-piperidyl)pyridine, Compound 30

2-nitro(1-piperidyl) pyridine was synthesized in a manner similar tothat used in the synthesis of2-nitro[4-(1-piperidyl)-1-piperidyl]pyridine. ¹HNMR (600 MHz, DMSO-d₆) δppm 1.56 (m, 6 H) 3.49 (d, J=4.39 Hz, 4 H) 7.30 - 7.47 (m, 1 H) 8.02 -8.12 (m, 1 H) 8.15 - 8.26 (m, 1 H).

Example 31 Synthesis of 5-(1-piperidyl)pyridin-2-amine, Compound 31

5-piperidyl) pyridin-2-amine was prepared in a manner similar to thatused in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.39 - 1.46 (m, 2 H) 1.51 - 1.62 (m, 4 H)2.75 - 2.92 (m, 4 H) 5.30 (s, 2 H) 6.34 (d, J=8.78 Hz, 1 H) 7.09 (dd,J=8.78, 2.93 Hz, 1 H) 7.54 (d, J=2.93 Hz, 1 H). LCMS (ESI) 178 (M + H).

Example 32 Synthesis of 4-(6-nitro-3-pyridyl) Thiomorpholine, Compound32

4-nitro-3-pyridyl) thiomorpholine was synthesized in a manner similar tothat used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 2.56 - 2.69 (m, 4 H) 3.79 - 3.92 (m, 4 H) 7.43 (dd,J=9.22, 3.07 Hz, 1 H) 8.10 (d, J=9.37 Hz, 1 H) 8.20 (d, J=2.93 Hz, 1 H).

Example 33 Synthesis of 5-thiomorpholinopyridin-2-amine, Compound 33

5-thiomorpholinopyridin-2-amine was prepared in a manner similar to thatused in the synthesis of 5-(4-methylpiperazin-1-yl) pyridin-2-amine.¹HNMR (600 MHz, DMSO-d₆) δ ppm 2.59 - 2.73 (m, 4 H) 3.04 - 3.20 (m, 4 H)5.41 (s, 2 H) 6.35 (d, J=8.78 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H)7.57 (d, J=2.64 Hz, 1 H). LCMS (ESI) 196 (M + H).

Example 34 Synthesis of Tert-butyl(4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-Carboxylate,Compound 34

tert-butyl(4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylatewas synthesized in a manner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.33 (d, J=32.21 Hz, 11 H) 1.91 (m, 2 H) 3.15 (d, J=10.25Hz, 1 H) 3.58 (m, 1 H) 4.46 (m, 1 H) 4.83 (s, 1 H) 7.16 (s, 1 H) 7.94(s, 1 H) 8.05-8.16 (m, 1 H).

Example 35 Synthesis of Tert-butyl(4R)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-Carboxylate,Compound 35

tert-butyl(4R)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylatewas prepared in a manner similar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine. ¹HNMR (600 MHz, DMSO-d₆) δppm 1.31 (d, J=31.91 Hz, 11 H) 1.83 (m, 2 H) 2.71 -2.82 (m, 1 H) 3.44(m,1 H) 4.30 (d, 2H) 5.08 (s, 2 H) 6.35 (d, J=8.78 Hz, 1 H) 6.77 - 6.91(m, 1 H) 7.33 (s, 1 H). LCMS (ESI) 291 (M + H).

Example 36 Synthesis of N,N-dimethyl-1-(6-nitro-3-pyridyl)Piperidin-4-amine, Compound 36

N,N-dimethyl-1-(6-nitro-3-pyridyl)piperidin-4-amine was synthesized in amanner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.30 - 1.45 (m, 2 H) 1.79 (m, 2 H) 2.14 (s, 6 H) 2.33 (m,1 H) 2.92 - 3.04 (m, 2 H) 4.03 (d, J=13.76 Hz, 2 H) 7.42 (dd, J=9.22,3.07 Hz, 1 H) 8.04 - 8.11 (m, 1 H) 8.21 (d, J=2.93 Hz, 1 H).

Example 37 Synthesis of 5-[4-(dimethylamino)-1-piperidyl]Pyridin-2-amine, Compound 37

5-(dimethylamino)-1-piperidyl]pyridin-2-amine was prepared in a mannersimilar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine. ¹HNMR (600 MHz, DMSO-d₆) δppm 1.35 - 1.50 (m, 2 H) 1.69 - 1.81 (m, 2 H) 2.00 - 2.10 (m, 1 H)2.11 - 2.22 (s, 6 H) 3.17 - 3.36 (m, 4 H) 5.19 - 5.38 (s, 2 H) 6.34 (d,J=8.78 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.63 Hz, 1H). LCMS (ESI) 221 (M + H).

Example 38 Synthesis of 4-(6-nitro-3-pyridyl) Morpholine, Compound 38

4-nitro-3-pyridyl) morpholine was synthesized in a manner similar tothat used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.

Example 39 Synthesis of 5-morpholinopyridin-2-amine, Compound 39

5-morpholinopyridin-2-amine was prepared in a manner similar to thatused in the synthesis of 5-(4-methylpiperazin-1-yl) pyridin-2-amine.¹HNMR (600 MHz, CHLOROFORM-d) δ ppm 2.91 - 3.00 (m, 4 H) 3.76 - 3.84 (m,4 H) 4.19 (br. s., 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.12 (dd, J=8.78, 2.93Hz, 1 H) 7.72 (d, J=2.93 Hz, 1 H).

Example 40 Synthesis of 5-(4-isobutylpiperazin-1-yl) Pyridin-2-amine,Compound 40

1-isobutyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a mannersimilar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted5-(4-isobutylpiperazin-1-yl)pyridin-2-amine in a manner similar to thatused in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.¹HNMR (600 MHz, CHLOROFORM-d) δ ppm 0.88 (d, J=6.73 Hz, 6 H) 1.71 - 1.84(m, 1 H) 2.10 (d, J=7.32 Hz, 2 H) 2.46 - 2.58 (m, 4 H) 2.97 - 3.07 (m, 4H) 4.12 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.14 (dd, J=8.78, 2.93 Hz, 1H) 7.75 (d, J=2.93 Hz, 1 H). LCMS (ESI) 235 (M + H).

Example 41 Synthesis of 5-(4-isopropylpiperazin-1-yl) Pyridin-2-amine,Compound 41

1-isopropyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a mannersimilar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then convertedto 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine in a manner similar tothat used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.¹HNMR (600 MHz, CHLOROFORM-d) δ ppm 1.06 (d, J=6.44 Hz, 6 H) 2.59 - 2.75(m, 5 H) 2.97 - 3.10 (m, 4 H) 4.13 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H)7.15 (dd, J=9.08, 2.93 Hz, 1 H) 7.76 (d, J=2.93 Hz, 1 H). LCMS (ESI) 221(M + H).

Example 42 Synthesis of5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-amine, Compound 42

(2S,6R)-2,6-dimethyl-4-(6-nitro-3-pyridyl)morpholine was synthesized ina manner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then convertedto 5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-amine in a mannersimilar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine. ¹HNMR (600 MHz, CHLOROFORM-d)δ ppm 1.20 (d, J=6.44 Hz, 6 H) 2.27 - 2.39 (m, 2 H) 3.11 - 3.21 (m, 2 H)3.70 - 3.84 (m, 2 H) 4.15 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.12 (dd,J=8.78, 2.93 Hz, 1 H) 7.72 (d, J=2.63 Hz, 1 H). LCMS (ESI) 208 (M + H).

Example 43 Synthesis of5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridin-2-amine, Compound 43

(3S,5R)-3,5-dimethyl-1-(6-nitro-3-pyridyl)piperazine was synthesized ina manner similar to that used in the synthesis of2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then convertedto 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridin-2-amine in a mannersimilar to that used in the synthesis of5-(4-methylpiperazin-1-yl)pyridin-2-amine. ¹HNMR (600 MHz, CHLOROFORM-d)δ ppm 1.09 (d, J=6.44 Hz, 6 H) 2.20 (t, J=10.83 Hz, 2 H) 2.95 - 3.08 (m,2 H) 3.23 (dd, J=11.71, 2.05 Hz, 2 H) 4.13 (s, 2 H) 6.45 (d, J=8.78 Hz,1 H) 7.14 (dd, J=8.78, 2.93 Hz, 1 H) 7.73 (d, J=2.63 Hz, 1 H). LCMS(ESI) 207 (M + H).

Example 44 Synthesis of Compound 44

tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate

A solution of intermediate A in ethanol (100 mL) was hydrogenated under30 psi of hydrogen using 10% Pd/C (0.7 g) in a pressure bomb for 7 hrs.After filtration of the reaction mixture through CELITE™, the organiclayer was concentrated under vacuum to afford tert-butylN-(2-amino-3-methyl-butyl) carbamate (3.8 g).

To a solution of 5-bromo-2,4-dichloro-pyrimidine (7.11 g, 0.0312 mole)in ethanol (100 mL) was added diisopropylethyl amine (5.45 mL, 1.0 eq)and tert-butyl N-(2-amino-3-methylbutyl) carbamate (6.31 g, 0.0312mole). The reaction mixture was stirred at room temperature for 20 hrs.After concentration under vacuum, ethyl acetate and water were added.The organic layer was separated, dried with magnesium sulfate and thenconcentrated under vacuum. The crude product was purified by silica gelcolumn chromatography using hexane/ethyl acetate (0- 30%) to affordtert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.77 - 0.85 (d, J=6.5 Hz, 3 H)0.87 (d, J=6.73 Hz, 3 H) 1.31 - 1.39 (m, 9 H) 1.82 - 1.93 (m, 1 H) 2.94(d, J=5.56 Hz, 1 H) 3.08 - 3.22 (m, 2 H) 3.98 (d, J=8.20 Hz, 1 H) 6.96(d, J=8.78 Hz, 1 H) 8.21 (s, 1 H). LCMS (ESI) 393 (M + H).

tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylbutyl]carbamate

tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylbutyl]carbamatewas synthesized by hosting tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamateto Sonogoshira conditions as described for tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamatefollowed by subsequent treatment with TBAF as described in the synthesisof tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate.¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.11 (d, J=6.44 Hz, 3 H) 1.18 (t, J=7.03Hz, 6 H) 1.21 - 1.26 (m, 12 H) 2.88 (br. s., 1 H) 3.43 - 3.78 (m, 6 H)3.97 - 4.08 (m, 1 H) 5.61 (s, 1 H) 6.65 (s, 1 H) 6.71 - 6.78 (m, 1 H)8.87 (s, 1 H). LCMS (ESI) 441 (M + H).

7-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

To a solution tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamatein THF was added TBAF and the contents were heated at reflux for 3 hrs.Ethyl acetate and water were then added and the organic layer separated,dried with magnesium sulfate and then concentrated under vacuum. To thiscrude reaction was added acetic acid/water (9:1) and the contents werestirred for 12 hrs at room temperature. After concentration undervacuum, sat NaHCO₃ and ethyl acetate were added. The organic layer wasseparated, dried and then concentrated under vacuum. The crude reactionproduct thus obtained was dissolved in DMF, oxone was then added and thecontents stirred for 3 hrs. After addition of ethyl acetate, thereaction mixture was filtered through CELITE™ and concentrated undervacuum. Column chromatography of the crude product over silica gel usinghexane/ethyl acetate (0- 100%) afforded7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.85 (d, J=7.03 Hz, 3 H) 0.97 (d,J=6.73 Hz, 3 H) 1.52 (s, 9 H) 1.99 - 2.23 (m, 1 H) 3.98 (dd, J=14.05,3.51 Hz, 1 H) 4.47 - 4.71 (m, 2 H) 7.47 (s, 1 H) 9.17 (s, 1 H). LCMS(ESI) 383 (M + H).

Compound 44

To7-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid (0.050 g, 0.00013 mole) in DCM (1.5 mL) was added DIC (32.7 mg) andDMAP (10 mg). The contents were stirred for 2 hrs. Trifluoroacetic acid(0.4 mL) was then added and stirring continued for an additional 30minutes. After addition of satd NaHCO₃ to neutralize the excess acid,ethyl acetate was added and the organic layer separated, dried usingmagnesium sulfate and then concentrated under vacuum. The crude productwas purified by silica gel column chromatography using hexane/ethylacetate (0- 100%) to afford the product. ¹HNMR (600 MHz, DMSO-d₆) δ ppm0.72 (d, J=6.73 Hz, 3 H) 0.97 (d, J=6.73 Hz, 3 H) 2.09 -2.22 (m, 1 H)3.57 (dd, J=13.18, 4.98 Hz, 1 H) 3.72 (dd, J=13.61, 4.25 Hz, 1 H) 4.53(dd, J=8.05, 3.95 Hz, 1 H) 7.20 (s, 1 H) 8.34 (d, J=4.98 Hz, 1 H) 9.08(s, 1 H). LCMS (ESI) 265 (M + H).

Example 45 Synthesis of Compound 45

Compound 14 was hydrogenated with 10% Pd/C to afford the intermediatetert-butyl N-[(2R)-2-amino-3-methyl-butyl] carbamate, which was thentreated with 5-bromo-2,4-dichloro-pyrimidine using analogous reactionconditions as described for Compound 44 to afford Compound 45 Theanalytical data is consistent with that reported for the racemate(Intermediate 1A).

Example 46 Synthesis of Compound 46

Compound 15 was hydrogenated with 10% Pd/C to afford the intermediatetert-butyl N-[(2S)-2-amino-3-methyl-butyl]carbamate, which was thentreated with 5-bromo-2,4-dichloro-pyrimidine using analogous reactionconditions as described for Compound 44 to afford Compound 46. Theanalytical data (NMR and LCMS) was consistent with that reported for theracemate Compound 44.

Example 47 Synthesis of Compound 47

To a solution of Compound 44 (80 mg, 0.00030 mole) in DMF (3 mL) wasadded a 60% dispersion of sodium hydride in oil (40 mg). After stirringfor 15 minutes, methyl iodide (37 µL, 2eq) was added. The contents werestirred at room temperature for 30 minutes. Saturated NaHCO₃ was thenadded followed by ethyl acetate. The organic layer was dried withmagnesium sulfate and then concentrated under vacuum to afford theproduct. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.74 (d, J=6.73 Hz, 3 H) 0.91(d, J=6.73 Hz, 3 H) 2.04 - 2.20 (m, 1 H) 3.04 (s, 3 H) 3.69 (dd,J=13.76, 1.17 Hz, 1 H) 3.96 (dd, J=13.76, 4.68 Hz, 1 H) 4.58 (dd,J=7.32, 3.51 Hz, 1 H) 7.16 (s, 1 H) 9.05 (s, 1 H). LCMS (ESI) 279 (M +H).

Example 48 Synthesis of Compound 48

tert-butylN-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate

Compound 18 was hydrogenated with 10% Pd/C in ethanol under a blanket ofhydrogen at 50 psi in a pressure bomb to afford tert-butylN-[(2S)-2-amino-4-methyl-pentyl]carbamate which was then reacted with5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions asdescribed for tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methylbutyl]carbamate toafford tert-butylN-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate.¹HNMR (600 MHz, CHLOROFORM-d) δ ppm 0.91 (d, J=6.44 Hz, 3 H) 0.94 (d,J=6.44 Hz, 3 H) 1.32 - 1.51 (m, 11 H) 1.55 - 1.67 (m, 1 H) 3.28 (t,J=5.86 Hz, 2 H) 4.21 - 4.42 (m, 1 H) 4.84 (s, 1 H) 5.84 (d, J=7.32 Hz, 1H) 8.07 (s, 1 H). LCMS (ESI) 407 (M + H).

To a solution of tert-butylN-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate(5.0 g, 12.3 mmole) in tolune (36 mL) and triethylamine (7.2 mL) wasadded under nitrogen, 3,3-diethoxyprop-1-yne (2.8 mL, 19.7 mmole),Pd₂(dba)₃ (1.1 g, 1.23 mmole), and triphenylarsine (3.8 g, 12.3 mmole).The contents were heated to 70 degrees for 24 hrs. After cooling to roomtemperature, the reaction mixture was filtered through CELITE™ and thenconcentrated under vacuum. The crude product was purified by silica gelcolumn chromatography using hexane/ethyl acetate (0- 30%) to afford(2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.LCMS (ESI) 455 (M + H).

7-[(1S)[(tert-butoxycarbonylamino)methyl]-3-methyl-butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using the analogous synthetic sequence as thatdescribed for7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.88 (d, J=6.44 Hz, 3 H) 0.97 (d,J=6.44 Hz, 3 H) 1.47 (s, 9 H) 1.49 - 1.54 (m, 1 H) 1.56 (t, J=7.17 Hz, 2H) 3.98 (dd, J 13.91, 3.07 Hz, 1 H) 3.76 (dd, J=13.31, 4.13 Hz, 1 H)4.38 (d, J=14.05 Hz, 1 H) 4.90 (t, J=7.17 Hz, 1 H) 7.41 (s, 1 H) 9.11(s, 1 H). LCMS (M + H) 397.

Compound 48 was synthesized using an analogous synthetic sequence asthat described for Compound 44. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.82 (d,J=6.73 Hz, 3 H) 0.97 (d, J=6.44 Hz, 3 H) 1.34 - 1.46 (m, 1 H) 1.48 -1.65 (m, 2 H) 3.40 (dd, J=13.32, 5.42 Hz, 1 H) 3.76 (dd, J=13.47, 4.10Hz, 1 H) 4.76 - 4.92 (m, 1 H) 7.17 (s, 1 H) 8.34 (d, J=5.27 Hz, 1 H)9.04 (s, 1 H). LCMS (ESI) 279 (M + H).

Example 49 Synthesis of Compound 49

Compound 49 was synthesized in a manner similar to that described forCompound 47. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.82 (d, J=6.44 Hz, 3 H)0.97 (d, J=6.44 Hz, 3 H) 1.37 -1.68 (m, 3 H) 3.04 (s, 3 H) 3.56 (d,J=13.47 Hz, 1 H) 4.00 (dd, J=13.32, 4.25 Hz, 1 H) 4.82 - 4.94 (m, 1 H)7.16 (s, 1 H) 9.03 (s, 1 H). LCMS (ESI) 293 (M + H).

Example 50 Synthesis of Compound 50

tert-butylN-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-pentyl]carbamate

Compound 20 was hydrogenated using 10% Pd/C under hydrogen at 50 psi ina pressure vessel to afford tert-butylN-[(2S)-2-amino-3-methyl-pentyl]carbamate which was reacted with5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions asdescribed for tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamateto afford tert-butylN-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-pentyl]carbamate.¹HNMR (600 MHz, CHLOROFORM-d) δ ppm 0.88 - 0.95 (m, 6 H) 1.11 - 1.20 (m,1 H) 1.34 (s, 9 H) 1.44 -1.54 (m, 1 H) 1.64 - 1.72 (m, 1 H) 3.17 - 3.27(m, 1 H) 3.33 - 3.43 (m, 1 H) 4.11 - 4.21 (m, 1 H) 4.81 (s, 1 H) 5.92(d, J=8.20 Hz, 1 H) 8.05 (s, 1 H). LCMS (ESI) 407.

tert-butylN-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-3-methylpentyl]carbamate

tert-butylN-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-3-methyl-pentyl]carbamatewas synthesized using similar experimental conditions to that used inthe synthesis of(2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methylpentane-1,2-diamine.¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.76 - 0.89 (m, 6 H) 1.03 (q, J=7.22 Hz,3 H) 1.10 - 1.17 (m, 3 H) 1.25 - 1.42 (m, 11 H) 1.59 - 1.73 (m, 1 H)3.35 - 3.47 (m, 4 H) 3.51 - 3.73 (m, 2 H) 3.99 - 4.11 (m, 1 H) 5.52 -5.56 (m, 1 H) 6.76 - 7.03 (m, 2 H) 8.12 - 8.23 (m, 1 H). LCMS (ESI) 455(M + H).

7-[(S)[(tert-butoxycarbonylamino)methyl]-2-methyl-butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

7-[(1S)[(tert-butoxycarbonylamino)methyl]-2-methyl-butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using the analogous synthetic sequence as thatdescribed for7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.80 (t, J=7.47 Hz, 3 H) 0.86 (d,J=7.03 Hz, 3 H) 1.06 - 1.30 (m, 2 H) 1.48 (s, 9 H) 1.79 - 1.96 (m, 1 H)3.95 (dd, J=14.05, 3.22 Hz, 1 H) 4.52 (d, J=14.35 Hz, 1 H) 4.61 - 4.73(m, 1 H) 7.43 (s, 1 H) 9.13 (s, 1 H). LCMS (ESI) 397 (M + H).

Compound 50 was synthesized using an analogous synthetic sequence asthat described for Compound 44. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.74 (t,J=7.32 Hz, 3 H) 0.89 (d, J=6.73 Hz, 3 H) 1.00 - 1.12 (m, 2 H) 1.82 -1.94 (m, 1 H) 3.55 (dd, J 13.91, 4.83 Hz, 1 H) 3.70 (dd, J=13.61, 4.25Hz, 1 H) 4.57 (dd, J=7.91, 4.10 Hz, 1 H) 7.17 (s, 1 H) 8.31 (d, J=5.27Hz, 1 H) 9.05 (s, 1 H). LCMS (ESI) 279 (M + H).

Example 51 Synthesis of Compound 51

Compound 51 was synthesized in a manner similar to Compound 47 . ¹HNMR(600 MHz, DMSO-d₆) δ ppm 0.77 (t, J=7.47 Hz, 3 H) 0.84 (d, J=6.73 Hz, 3H) 1.07 - 1.16 (m, 2 H) 1.82 -1.95 (m, 1 H) 3.03 (s, 3 H) 3.68 (d,J=13.76 Hz, 1 H) 3.96 (dd, J=13.76, 4.39 Hz, 1 H) 4.59 - 4.70 (m, 1 H)7.16 (s, 1 H) 9.04 (s, 1 H). LCMS (ESI) 293 (M + H).

Example 52 Synthesis of Compound 52

tert-butylN-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3,3-dimethyl-butyl]carbamate

Compound 21 was hydrogenated using 10% Pd/C under hydrogen at 50 psi ina pressure vessel to afford tert-butylN-[(2S)-2-amino-3,3-dimethyl-butyl]carbamate which was then reacted with5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions asdescribed using analogous reaction conditions as described fortert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamateto afford tert-butylN-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3,3-dimethyl-butyl]carbamate.LCMS (ESI) 407 (M + H).

tert-butylN-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]-3,3-dimethylbutyl]carbamate

tert-butylN-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-3,3-dimethyl-butyl]carbamatewas synthesized using similar experimental conditions to that used inthe synthesis of(2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methylpentane-1,2-diamine.LCMS (ESI) 455 (M + H).

7-[(1S)[(tert-butoxycarbonylamino)methyl]-2,2-dimethyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

7-[(1S)[(tert-butoxycarbonylamino)methyl]-2,2-dimethyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using the analogous synthetic sequence as thatdescribed for7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. LCMS (ESI) 397 (M + H).

Intermediate 1F was synthesized using an analogous synthetic sequence asthat described for intermediate 1A. LCMS (ESI) 279 (M + H).

Example 53 Synthesis of Compound 53

Compound 53 was synthesized in a manner similar to that described forIntermediate 1CA. LCMS (ESI) 293 (M + H).

Example 54 Synthesis of Compound 54

tert-butylN-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-phenyl-ethyl]carbamate

Compound 21 was hydrogenated using 10% Pd/C under hydrogen at 50 psi ina pressure vessel to afford tert-butylN-[(2S)-2-amino-2-phenyl-ethyl]carbamate which was then reacted with5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions asdescribed for tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamateto afford tert-butylN-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-phenyl-ethyl]carbamate.¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.32 (s, 9 H) 3.29 - 3.50 (m, 2 H) 5.12 -5.24 (m, 1 H) 7.10 (t, J=5.27 Hz, 1 H) 7.21 (t, J=6.88 Hz, 1 H) 7.26 -7.34 (m, 4 H) 7.89 (d, J=7.32 Hz, 1 H) 8.24 (s, 1 H). LCMS (ESI) 427(M + H).

tert-butylN-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]-2-phenylethyl]carbamate

tert-butylN-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-phenyl-ethyl]carbamatewas synthesized using similar experimental conditions to those used inthe synthesis of(2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methylpentane-1,2-diamine.¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.14 (t, J=7.03 Hz, 6 H) 1.32 (s, 9 H)3.39 (s, 2 H) 3.52 - 3.61 (m, 2 H) 3.64 - 3.73 (m, 2 H) 5.17 - 5.26 (m,1 H) 5.57 (s, 1 H) 7.07 -7.14 (m, 1 H) 7.20 - 7.25 (m, 1 H) 7.26 - 7.33(m, 4 H) 7.90 (d, J=7.61 Hz, 1 H) 8.19 (s, 1 H). LCMS (ESI) 475 (M + H).

7-[(1S)(tert-butoxycarbonylamino)-1-phenyl-ethyl]chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

7-[(1S)(tert-butoxycarbonylamino)-1-phenyl-ethyl]chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using the analogous synthetic sequence as thatdescribed for7-[1-[(tert-butoxycarbonylamino)methyl]methyl-propyl]chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. LCMS (ESI) 417 (M + H).

Compound 54

Compound 54 was synthesized using an analogous synthetic sequence asthat described for Compound 44. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 3.58 -3.69 (m, 1 H) 4.13 (dd, J=13.47, 4.39 Hz, 1 H) 6.07 (d, J=3.81 Hz, 1 H)6.85 (d, J=7.32 Hz, 2 H) 7.19 - 7.31 (m, 3 H) 7.34 (s, 1 H) 8.27 (d,J=5.27 Hz, 1 H) 9.13 (s, 1 H). LCMS (ESI) 299 (M + H).

Example 55 Synthesis of Compound 55

tert-butylN-[(1S)-1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]-2-methyl-propyl]carbamate

tert-butylN-[(1S)-1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]-2-methylpropyl]carbamatewas synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate Eusing analogous reaction conditions as described for tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.¹HNMR (600 MHz, CHLOROFORM-d) δ ppm 0.95 - 1.02 (m, 6 H) 1.35 - 1.45 (m,9 H) 1.75 - 1.90 (m, 1 H) 3.35 - 3.48 (m, 1 H) 3.52 -3.61 (m, 1 H)3.64 - 3.76 (m, 1 H) 4.56 (d, J=8.49 Hz, 1 H) 6.47 (s, 1 H) 8.07 (s, 1H). LCMS (ESI) 393 (M + H).

tert-butylN-[(1S)-1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]-2-methyl-propyl]carbamate

tert-butylN-[(1S)-1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]-2-methyl-propyl]carbamatewas synthesized using similar experimental conditions to those used inthe synthesis(2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.¹HNMR (600 MHz, CHLOROFORM-d) δ ppm 0.90 - 1.00 (m, 6 H) 1.18- 1.25 (m,6 H) 1.34 - 1.36 (m, 9 H) 1.69 - 1.90 (m, 1 H) 3.34 -3.82 (m, 6 H)4.53 - 4.77 (m, 1 H) 5.45 - 5.55 (m, 1 H) 6.37 (dd, J=15.37, 6.59 Hz, 1H) 6.56 (s, 1 H) 8.05 (s, 1 H). LCMS (ESI) 441 (M + H).

7-[(2S)(tert-butoxycarbonylamino)-3-methyl-butyl]chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

7-[(2S)(tert-butoxycarbonylamino)-3-methyl-butyl]chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using the analogous synthetic sequence as thatdescribed for7-[1-[(tert-butoxycarbonylamino)methyl]methyl-propyl]chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. ¹HNMR (600 MHz, CHLOROFORM-d) δ ppm 0.90 (d, J=6.73 Hz, 3 H) 0.96(d, J=7.03 Hz, 3 H) 1.55 - 1.66 (m, 10 H) 4.14 (dd, J=13.61, 3.95 Hz, 1H) 4.52 -4.63 (m, 1 H) 4.84 (dd, J=13.61, 1.32 Hz, 1 H) 7.37 (s, 1 H)8.95 (s, 1 H). LCMS (ESI) 383 (M + H).

Compound 55

Compound 55 was synthesized using an analogous synthetic sequence asthat described for Compound 44. LCMS (ESI) 265 (M + H).

Example 56 Synthesis of Compound 56

Compound 56 was synthesized using 5-bromo-2,4-dichloro-pyrimidine andCompound 17 as starting materials, and following a similar sequence ofsynthetic steps as for Compound 55. The analytical data was consistentwith that described for its antipode (Compound 55). ¹HNMR (600 MHz,DMSO-d₆) δ ppm 0.88 (d, J=6.44 Hz, 6 H) 1.73 - 1.86 (m, 1 H) 3.67 - 3.76(m, 2 H) 4.11 -4.21 (m, 1 H) 7.13 - 7.19 (m, 1 H) 8.56 (s, 1 H) 9.05 (s,1 H). LCMS (ESI) 265 (M + H).

Example 57 Synthesis of Compound 57

tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate

tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamatewas synthesized using 5-bromo-2,4-dichloro-pyrimidine and tert-butylN-(2-amino-2-methylpropyl)carbamate using analogous reaction conditionsas described for tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.LCMS (ESI) 379 (M + H).

tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]-2-methylpropyl]carbamate

tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]-2-methylpropyl]carbamatewas synthesized using similar experimental conditions to those used inthe synthesis of(2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.11 - 1.22 (m, 6 H) 1.31 - 1.45 (m, 15H) 3.10 - 3.24 (m, 2 H) 3.51 - 3.76 (m, 4 H) 5.60 (s, 1 H) 6.94 (s, 1 H)7.33 (t, J=6.44 Hz, 1 H) 8.18 (s, 1 H). LCMS (ESI) 427 (M + H).

7-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

7-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using the analogous synthetic sequence as thatdescribed for7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.43 (s, 9H) 1.73 (s, 6 H) 4.06 (s,2 H) 7.46 (s, 1 H) 9.23 (s, 1H). LCMS (ESI) 369 (M + H).

Compound 57

Compound 57 was synthesized using an analogous synthetic sequence asthat described for Compound 44. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.73 (s,6 H) 3.50 (d, J=2.93 Hz, 2 H) 7.25 (s, 1 H) 8.46 - 8.55 (m, 1 H) 9.07(s, 1 H). LCMS (ESI) 251 (M + H).

Example 58 Synthesis of Compound 58

tert-butylN-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclohexyl]methyl]carbamate

tert-butylN-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclohexyl]methyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine andIntermediate K using the analogous reaction conditions as described fortert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.18 - 1.54 (m, 17 H) 2.23 (d,J=14.35 Hz, 2 H) 3.36 (d, J=6.44 Hz, 2 H) 5.82 (s, 1 H) 6.93 (s, 1 H)8.22 (s, 1 H). LCMS (ESI) 419 (M + H).

tert-butylN-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclohexyl]methyl] carbamate

tert-butylN-[[1-[[2-chloro-5-(3,3-diethoxyprop1-ynyl)pyrimidin-4-yl]amino]cyclohexyl]methyl]carbamate was synthesized using similar experimental conditions to thoseused in the synthesis of(2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.08 - 1.16 (m, 6 H) 1.17 - 1.54 (m, 17H) 2.13 (br. s., 2 H) 3.36 (d, J=6.73 Hz, 2 H) 3.50 - 3.69 (m, 4 H) 5.72(s, 1 H) 6.94 (s, 1 H) 5.72 (br. s., 1H) 8.17 (s, 1 H). LCMS (ESI) 467(M + H).

7-[(tert-butoxycarbonylamino)methyl]cyclohexyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

7-[(tert-butoxycarbonylamino)methyl]cyclohexyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using analogous synthetic sequence as thatdescribed for7-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.37 - 1.54 (m, 13 H) 1.75 (br. s.,4 H) 2.74 (br. s., 2 H) 3.78 - 3.84 (m, 2 H) 7.44 - 7.51 (m, 1 H) 8.23(s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 409 (M + H).

Compound 58

Compound 58 was synthesized using an analogous synthetic sequence asthat described for Compound 44. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.28 (br.s., 2 H) 1.42 (br. s., 2 H) 1.70 (br. s., 4 H) 1.85 - 1.95 (m, 2 H) 2.69(m, 2 H) 7.16 - 7.25 (m, 1 H) 8.41 (br. s., 1 H) 9.04 (s, 1 H). LCMS 291(M + H).

Example 59 Synthesis of Compound 59

tert-butylN-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamate

tert-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl] carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidineand Intermediate L using analogous reaction conditions as described fortert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.34 (s, 9 H) 1.50 -1.58 (m, 2 H) 1.63 -1.78 (m, 4 H) 1.96 - 2.06 (m, 2 H) 3.25 (d, J=6.15 Hz, 2 H) 6.71 (s, 1H) 7.18 (t, J=6.29 Hz, 1 H) 8.20 (s, 1 H). LCMS (ESI) 405 (M + H).

tert-butylN-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]methyl] carbamate

tert-butylN-[[1-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]cyclopentyl]methyl]carbamatewas synthesized using similar experimental conditions to that used inthe synthesis of(2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.LCMS (ESI) 453 (M + H).

7-[(tert-butoxycarbonylamino)methyl]cyclopentyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

7-[(tert-butoxycarbonylamino)methyl]cyclopentyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using the analogous synthetic sequence as thatdescribed for7-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.47 (s, 9 H) 1.74 (br. s., 2 H)1.88 (br. s., 2 H) 2.04 (br. s., 2 H) 2.41 - 2.45 (m, 2 H) 4.06 (s, 2 H)7.45 (s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 395 (M + H).

Compound 59

Compound 59 was synthesized using an analogous synthetic sequence asthat described for Compound 44. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.72 (br.s., 2 H) 1.86 - 1.93 (m, 2 H) 1.99 (d, J=3.81 Hz, 2 H) 2.40 (br. s., 2H) 3.48 (d, J=2.34 Hz, 2 H) 7.22 (s, 1 H) 8.53 (br. s., 1 H) 9.05 (s, 1H). LCMS (ESI) 277 (M + H).

Example 60 Synthesis of Compound 60

tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl] carbamate

tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamatewas synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate Busing analogous reaction conditions as described for tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.The analytical data is consistent with that described for theL-enantiomer.

tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]-4-methyl-pentyl]carbamate

tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]-4-methylpentyl]carbamatewas synthesized using similar experimental conditions to that used inthe synthesis of tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate.¹HNMR (600 MHz, CHLOROFORM-d) δ ppm 1.21 - 1.31 (m, 12 H) 1.38 - 1.46(m, 11 H) 1.70 (m, 1H) 3.24 (m, 2 H) 3.65 - 3.82 (m, 4 H) 4.86 (br s.,1H), 5.65 (s, 1 H) 5.85 (br s., 1H) 6.94 (s, 1 H) 8.21 (s, 1 H). LCMS(ESI) 455 (M + H).

7-[(tert-butoxycarbonylamino)methyl]-3-methyl-butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

7-[(tert-butoxycarbonylamino)methyl]-3-methyl-butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using analogous synthetic sequence as thatdescribed for7-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. The analytical data was consistent with that described for theL-isomer.

Compound 60

Compound 60 was synthesized using an analogous synthetic sequence asthat described for Compound 44. The analytical data was consistent withthat described for the L-isomer.

Example 61 Synthesis of Compound 61

To a solution of Compound 60 (100 mg, 0.00024 mole) in DMF (3.0 mL) wasadded sodium hydride (60 % dispersion in oil), (27.6 mg, 3 eq). Afterstirring for 15 mins, methyl iodide (30, 2 eq) was added. The contentswere stirred at room temperature for 30 mins. After the addition of satNaHCO₃, ethyl acetate was added. Separation of the organic layerfollowed by drying with magnesium sulfate and concentration under vacuumafforded the product. Analytical data was similar to the Compound 49.

Example 62 Synthesis of Compound 62

tert-butylN-[(1S,2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]carbamate

tert-butylN-[(1S,2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]carbamatewas synthesized by treating tert-butylN-[(1S,2S)-2-aminocyclopentyl]carbamate with5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions asdescribed for tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.27 (s, 9 H) 1.42 - 1.54 (m, 2 H) 1.56 -1.65 (m, 2 H) 1.80 - 1.88 (m, 1 H) 1.96 - 2.01 (m, 1 H) 3.88 - 3.96 (m,1 H) 4.03 - 4.09 (m, 1 H) 6.91 (d, J=8.20 Hz, 1 H) 7.41 (d, J=7.32 Hz, 1H) 8.18 (s, 1 H). LCMS (ESI) 391 (M + H).

tert-butylN-[(1S,2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]carbamate

tert-butylN-[(1S,2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]carbamatewas synthesized using similar experimental conditions to that used inthe synthesis of(2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.13 (t, 6 H) 1.28 (s, 9 H) 1.42 - 1.52(m, 2 H) 1.58 - 1.65 (m, 2 H) 1.81 - 1.90 (m, 1 H) 1.99 - 2.08 (m, 1 H)3.49 - 3.60 (m, 2 H) 3.63 - 3.71 (m, 2 H) 3.84 - 3.93 (m, 1 H) 3.96 -4.04 (m, 1 H) 5.53 (s, 1 H) 6.96 (d, J=7.90 Hz, 1 H) 7.34 (d, J=7.03 Hz,1 H) 8.14 (s, 1 H). LCMS (ESI) 439 (M + H).

7-[(1S,2S)-2-(tert-butoxycarbonylamino)cyclopentyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

7-[(1S,2S)-2-(tert-butoxycarbonylamino)cyclopentyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using the analogous synthetic sequence as thatdescribed for7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.41 - 1.52 (m, 9 H) 1.55 - 1.68(m, 1 H) 1.88 - 2.00 (m, 2 H) 2.05 - 2.15 (m, 1 H) 2.26 - 2.35 (m, 1 H)2.71 - 2.89 (m, 1 H) 4.01 - 4.16 (m, 1 H) 4.28 - 4.45 (m, 1 H) 7.41 (s,1 H) 9.11 (s, 1 H). LCMS (ESI) 381 (M + H).

Compound 62

Compound 62 was synthesized using an analogous synthetic sequence asthat described for Compound 44. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.48 -1.60 (m, 1 H) 1.88 - 1.98 (m, 3 H) 1.99 - 2.08 (m, 1 H) 2.66 - 2.75 (m,1 H) 3.63 - 3.74 (m, 1 H) 3.99 - 4.12 (m, 1 H) 7.21 (s, 1 H) 8.89 (s, 1H) 9.04 (s, 1 H). LCMS (ESI) 263 (M + H).

Example 63 Synthesis of Compound 63

To chloro tricycliclactam (0.050 g, 0.225 mmole) in dioxane (2.0 mL)under nitrogen was added 5-(4-methylpiperazin-1-yl)pyridin-2-amine(0.052 g, 1.2 eq, 0.270 mmole) followed by the addition of Pd₂(dba)₃(18.5 mg), BINAP (25 mg) and sodium-tert-butoxide ( 31 mg, 0.324 mmole).The contents of the flask are degassed for 10 minutes and then heated to100 degrees for 12 hours. The crude reaction was loaded on a silica gelcolumn and eluted with DCM/MeOH (0-15%) to afford the desired product(26 mg). To this compound dissolved in DCM/MeOH (10%) was added 3 N HC1in iso-propanol (2 eq) and the reaction was stirred overnight.Concentration under vacuum afforded the hydrochloride salt. ¹HNMR(d6-DMSO) δ ppm 11.13 (brs, 1H), 9.07 (s, 1H), 8.42 (s, 1H), 8.03 (br m1H), 7.99 (s, 1H), 7.67 (brm, 1H), 7.18 (s, 1H), 4.33 (m, 2H), 3.79 (m,2H), 3.64 (m, 2H), 3.50 (m, 2H), 3.16 (m, 4H), 2.79 (s, 3H). LCMS (ESI)379 (M + H).

Example 64 Synthesis of Compound 64

To chloro tricycliclactam (0.075 g, 0.338 mmole) in dioxane (3.5 mL)under nitrogen was added tert-butyl4-(6-amino-3-pyridyl)piperazine-1-carboxylate (0.098 g, 1.05 eq)followed by the addition of Pd₂(dba)₃ (27 mg), BINAP (36 mg) and sodium-tert-butoxide (45 mg). The contents were heated at reflux for 11 hrs.The crude reaction was loaded onto a silica gel column and eluted withDCM/MeOH (0- 10%) to afford the desired product (32 mg). ¹HNMR (d6-DMSO)δ ppm 9.48 (s, 1H), 8.84 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.99 (s,1H), 7.42 (m, 1H), 6.98 (s, 1H), 4.23 (m, 2H), 3.59 (m, 2H), 3.45 (m,4H), 3.50 (m, 2H), 3.05 (m, 4H). LCMS (ESI) 465 (M + H).

Example 65 Synthesis of Compound 65

To a solution of Compound 64 (23 mg) in 10% DCM/MeOH was added 10 mL ofa 3 M solution ofHCl in iso-propanol. The contents were stirred for 16hrs. Concentration of the reaction mixture afforded the hydrochloridesalt. ¹HNMR (d6-DMSO) δ ppm 9.01 (s, 1H), 7.94 (m, 1H), 7.86 (m, 1H),7.23 (s, 1H), 4.30 (m, 2H), 3.64 (m, 2H), 3.36 (m, 4H), 3.25 (m, 4H).LCMS (ESI) 465 (M + H).

Example 66 Synthesis of Compound 66

To chloro-N-methyltricyclic amide (0.080 g, 0.338 mmole) in dioxane (3.5mL) under nitrogen was added tert-butyl4-(6-amino-3-pyridyl)piperazine-1-carboxylate 0.102 g (1.1 eq) followedby the addition of Pd₂(dba)₃ (27 mg), BINAP (36 mg) and sodium-tert-butoxide (45 mg). The contents were heated at reflux for 11 hrs.The crude product was purified using silica gel column chromatographywith an eluent of dichloromethane/methanol (0- 5%) to afford the desiredproduct (44 mg). ¹HNMR (d6-DMSO) δ ppm 9.49 (s, 1H), 8.85 (s, 1H), 8.32(m, 1H), 8.02 (s, 1H), 7.44 (m, 1H), 7.00 (s, 1H), 4.33 (m, 2H), 3.80(m, 2H), 3.48 (m, 4H), 3.07 (m, 4H), 3.05 (s, 3H), 1.42 (s, 9H). LCMS(ESI) 479 (M + H).

Example 67 Synthesis of Compound 67

To Compound 66 (32 mg) was added 3 N HCL (10 mL) in isopropanol and thecontents were stirred at room temperature overnight for 16 hrs.Concentration afforded the hydrochloride salt. ¹HNMR (d6-DMSO) δ ppm9.13 (m, 2H), 8.11 (m, 1H), 8.10 (s, 1H), 7.62 (m, 1H), 7.21 (s, 1H),4.43 (m, 2H), 3.85 (m, 2H), 3.41 (m, 4H), 3.28 (m, 4H), 3.08 (s, 3H).LCMS (ESI) 379 (M + H).

Example 68 Synthesis of Compound 68

Compound 68 was synthesized using similar experimental conditions tothat described for compound 64. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.79 (d,J=7.03 Hz, 3 H) 1.01 (d, J=6.73 Hz, 3 H) 1.35 - 1.48 (m, 9 H) 2.16 (dd,J=14.64, 6.73 Hz, 1 H) 3.00 - 3.14 (m, 4 H) 3.40 - 3.51 (m, 4 H) 3.51 -3.60 (m, 1 H) 3.63 - 3.74 (m, 1 H) 4.44 (dd, J=7.90, 3.81 Hz, 1 H) 6.99(s, 1 H) 7.46 (dd, J=8.93, 2.78 Hz, 1 H) 7.94 - 8.09 (m, 2 H) 8.31 (dd,J=9.08, 1.46 Hz, 1 H) 8.85 (s, 1 H) 9.46 (s, 1 H). LCMS (ESI) 507 (M +H) .

Example 69 Synthesis of Compound 69

Compound 69 was synthesized using similar experimental conditions tothose described for compound 63 and was recovered as an HC1 salt. ¹HNMR(600 MHz, DMSO-d₆) δ ppm 0.77 -0.86 (m, 3 H) 0.96 (d, J=7.03 Hz, 3 H)2.10 - 2.24 (m, 1 H) 3.07 (s, 3 H) 3.37 - 3.79 (m, 8 H) 4.00 (dd,J=13.61, 4.54 Hz, 2 H) 4.63 - 4.73 (m, 1 H) 7.20 (s, 1 H) 7.58 - 7.71(m, 1 H) 7.99 (d, J=2.34 Hz, 1 H) 8.12 (d, J=9.37 Hz, 1 H) 9.11 (s, 1 H)9.41 (br. s., 2 H) 11.76 (br. s., 1 H). LCMS (ESI) 421 (M + H).

Example 70 Synthesis of Compound 70

Compound 70 was synthesized using similar experimental conditions tothose described for compounds 64 and 65 and was recovered as an HClsalt. The characterization data (NMR and LCMS) was consistent with thatreported for compound 71 .

Example 71 Synthesis of Compound 71

Compound 71 was synthesized using similar experimental conditions tothose described for compounds 64 and 65 and was recovered as an HClsalt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.79 (d, J=6.73 Hz, 3 H) 1.01 (d,J=6.73 Hz, 3 H) 2.18 (dd, J=14.49, 7.17 Hz, 1 H) 3.18 -3.84 (m, 10 H)4.53 - 4.71 (m, 1 H) 7.24 (s, 1 H) 7.65 (d, J=9.37 Hz, 1 H) 8.01 (d,J=2.64 Hz, 1 H) 8.14 (d, J=1.46 Hz, 1 H) 8.35 (d, J=5.27 Hz, 1 H) 9.14(s, 1 H) 9.46 (s, 2 H) 11.80 (s, 1 H) LCMS (ESI) 407 (M+H).

Example 72 Synthesis of Compound 72 (Compound UUU)

Compound 72 was synthesized using similar experimental conditions tothat described for compounds 64 and 65 and was recovered as an HC1 salt.¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.77 (d, J=7.03 Hz, 3 H) 0.99 (d, J=6.73Hz, 3 H) 2.10 - 2.24 (m, 1 H) 3.18 - 3.81 (m, 10 H) 4.54 - 4.69 (m, 1 H)7.22 (s, 1 H) 7.63 (d, J=9.08 Hz, 1 H) 7.99 (d, J=2.63 Hz, 1 H) 8.11 (s,1 H) 8.33 (d, J=5.27 Hz, 1 H) 9.12 (s, 1 H) 9.43 (s, 2 H) 11.77 (s, 1H). LCMS (ESI) 407 (M+H).

Example 73 Synthesis of Compound 73

Compound 73 was synthesized using similar experimental conditions tothose described for compounds 64 and 65 and was recovered as an HC1salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.84 (d, J=6.73 Hz, 3 H) 0.98 (d,J=6.73 Hz, 3 H) 2.12 - 2.26 (m, 1 H) 3.09 (s, 3 H) 3.22 -3.81 (m, 8 H)4.01 (dd, J=13.61, 4.25 Hz, 2 H) 4.59 - 4.72 (m, 1 H) 7.19 (s, 1 H) 7.74(s, 1 H) 7.96 - 8.10 (m, 2 H) 9.08 (s, 1 H) 9.22 (s, 2 H). LCMS (ESI)421 (M+H).

Example 74 Synthesis of Compound 74

Compound 74 was synthesized using similar experimental conditions tothose described for compound 63 and was recovered as an HC1 salt. ¹HNMR(600 MHz, DMSO-d₆) δ ppm 0.85 (d, J=4.98 Hz, 3 H) 0.95 (d, J=4.98 Hz, 3H) 1.42 - 1.70 (m, 3 H) 2.77 (d, J=2.93 Hz, 3 H) 3.07 -4.14 (m, 10 H)4.95 (s, 1 H) 7.20 (s, 1 H) 7.66 (d, J=9.66 Hz, 1 H) 7.94 (s, 1 H)8.08 - 8.16 (m, 1 H) 8.33 (d, J=4.68 Hz, 1 H) 9.09 (s, 1 H) 11.38 (s, 1H) 11.71 (s, 1 H). LCMS (ESI) 435 (M+H).

Example 75 Synthesis of Compound 75

Compound 75 was synthesized using similar experimental conditions tothose described for compounds 64 and 65 and was recovered as an HC1salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.87 (d, J=6.15 Hz, 3 H) 0.94 (d,J=6.15 Hz, 3 H) 1.57 (d, J=84.61 Hz, 3 H) 3.05 (s, 3 H) 3.13 - 3.55 (m,8 H) 3.69 (d, J=78.17 Hz, 2 H) 4.90 (s, 1 H) 7.15 (s, 1 H) 7.63 - 7.85(m, 1 H) 7.93 (s, 1 H) 8.26 (s, 1 H) 9.03 (s, 1 H) 9.20 (s, 2 H). LCMS(ESI) 421 (M+H).

Example 76 Synthesis of Compound 76

Compound 76 was synthesized using similar experimental conditions tothose described for compound 63 and was recovered as an HC1 salt. ¹HNMR(600 MHz, DMSO-d₆) δ ppm 0.85 (d, J=6.44 Hz, 3 H) 0.95 (d, J=6.44 Hz, 3H) 1.43 - 1.70 (m, 3 H) 2.78 (d, J=2.93 Hz, 3 H) 3.05 (s, 3 H) 3.24 -3.84 (m, 8 H) 4.01 (d, J=9.66 Hz, 2 H) 4.89 - 5.01 (m, 1 H) 7.15 (s, 1H) 7.77 (s, 1 H) 7.91 - 8.05 (m, 2 H) 9.03 (s, 1 H) 10.96 - 11.55 (m, 2H). LCMS (ESI) 449 (M+H).

Example 77 Synthesis of Compound 77

Compound 77 was synthesized using similar experimental conditions tothose described for compounds 64 and 65 and was recovered as an HC1salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.83 - 0.88 (d, J=6.15 Hz, 3 H)0.95 (d, J=6.15 Hz, 3 H) 1.40 - 1.71 (m, 3 H) 3.28 - 3.83 (m, 8 H) 4.00(d, J=3.22 Hz, 2 H) 4.91 - 5.08 (m, 1 H) 7.17 (s, 1 H) 7.68 (d, J=9.66Hz, 1 H) 7.93 (s, 1 H) 8.07 (s, 1 H) 9.06 (s, 1 H) 9.40 (s, 2 H) 11.59(s, 1 H). LCMS (ESI) 435 (M+H).

Example 78 Synthesis of Compound 78

To Compound 50 0.060 g (0.205 mmole) was added5-(4-methylpiperazin-1-yl)pyridin-2-amine (35.42 mg, 0.9 eq) followed bythe addition of 1,4-dioxane (3 mL). After degassing with nitrogen,Pd₂dba₃ (12 mg), BINAP (16 mg) and sodium tert-butoxide (24 mg) wereadded. The contents were then heated at 90 degrees in a CEM Discoverymicrowave for 3 hrs. The reaction was then loaded onto a silica gelcolumn and purified by eluting with DCM/MeOH (0- 15%). ¹HNMR (600 MHz,DMSO-d₆) δ ppm 0.75 (t, J=7.47 Hz, 3 H) 0.91 (d, J=6.73 Hz, 3 H) 1.04-1.20 (m, 2 H) 1.80 - 1.98 (m, 1 H) 2.77 (d, J=3.81 Hz, 3 H) 2.94 - 3.90(m, 10 H) 4.54 - 4.68 (m, 1 H) 7.06 - 7.23 (m, 2 H) 7.56 - 7.75 (m, 1 H)7.90 - 8.12 (m, 2 H) 8.29 (s, 1 H) 9.07 (s, 1 H) 10.98 - 11.74 (m, 2 H).LCMS (ESI) 435 (M + H).

Example 79 Synthesis of Compound 79

Compound 79 was synthesized in a similar manner to that described forcompound 78 followed by the deblocking step described for compound 65and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.75(t, J=7.32 Hz, 3 H) 0.90 (d, J=.6.73 Hz, 3 H) 1.07 -1.15 (m, 2H) 1.85 -1.94 (m, 1 H) 3.17 - 3.75 (m, 10 H) 4.58 - 4.67 (m, 1 H) 7.17 (s, 1 H)7.71 (s, 1 H) 7.96 (s, 1 H) 7.98 - 8.05 (m, 1 H) 8.28 (d, J=4.10 Hz, 1H) 9.06 (s, 1 H) 9.39 (s, 2 H). LCMS (ESI) 421 (M+H).

Example 80 Synthesis of Compound 80

Compound 80 was synthesized in a similar manner to that described forcompound 78. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.78 (t, J=7.32 Hz, 3 H)0.86 (d, J=6.73 Hz, 3 H) 1.13 -1.21 (m, 2 H) 1.84 - 1.96 (m, 1 H) 2.77(d, J=4.39 Hz, 3 H) 3.04 (s, 3 H) 3.11 - 3.84 (m, 8 H) 3.98 (dd,J=13.61, 4.25 Hz, 2 H) 4.66 - 4.74 (m, 1 H) 7.17 (s, 1 H) 7.64 (s, 1 H)7.96 (d, J=2.34 Hz, 1 H) 8.03 - 8.13 (m, 1 H) 9.08 (s, 1 H) 11.26 (s, 1H) 11.66 (s, 1 H). LCMS (ESI) 449 (M+H).

Example 81 Synthesis of Compound 81

The compound was synthesized in a similar manner to that described forcompound 78 followed by the deblocking step described for compound 65and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.78(t, J=7.32 Hz, 3 H) 0.85 (d, J=6.73 Hz, 3 H) 1.10 -1.27 (m, 2 H) 1.82 -1.99 (m, 1 H) 3.04 (s, 3 H) 3.28 - 3.77 (m, 8 H) 3.97 (dd, J 13.91, 4.54Hz, 2 H) 4.62 - 4.75 (m, 1 H) 7.07 - 7.24 (m, 1 H) 7.62 - 7.75 (m, 1 H)7.94 (d, J=2.34 Hz, 1 H) 7.97 -8.08 (m, 1 H) 9.05 (s, 1 H) 9.29 (s, 2H). LCMS (ESI) 435 (M+H).

Example 82 Synthesis of Compound 82

The compound was synthesized in a similar manner to that described forcompound 78 followed by the deblocking step described for compound 65and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.96(s, 9 H) 3.15 - 3.87 (m, 10 H) 4.42 - 4.53 (m, 1 H) 6.99 (s, 1 H) 7.24(s, 1 H) 8.06 (s, 1 H) 8.11 - 8.21 (m, 1 H) 8.79 - 8.98 (m, 2 H) 9.25(s, 2 H) 9.88 (s, 1 H). LCMS (ESI) 421 (M+H).

Example 83 Synthesis of Compound 83

Compound 83 was synthesized in a similar manner to that described forcompound 78 followed by the deblocking step described for compound 65and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.95(s, 9 H) 2.79 (d, J=4.10 Hz, 3 H) 3.06 - 3.86 (m, 10 H) 4.56 - 4.67 (m,1 H) 7.17 (s, 1 H) 7.70 (s, 1 H) 7.96 (d, J=2.63 Hz, 1 H) 7.99 - 8.08(m, 1 H) 8.26 (s, 1 H) 9.06 (s, 1 H) 10.80 (s, 1 H). LCMS (ESI) 435(M+H).

Example 84 Synthesis of Compound 84

Compound 84 was synthesized in a similar manner to that described forcompound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δppm 2.75 - 2.81 (m, 3 H) 3.12 -3.16 (m, 2 H) 3.46 - 3.54 (m, 4 H) 3.60 -3.69 (m, 2 H) 3.72 - 3.79 (m, 1 H) 4.07 - 4.18 (m, 2 H) 6.06 - 6.09 (m,1 H) 6.90 (d, J=7.61 Hz, 2 H) 7.20 - 7.31 (m, 3 H) 7.33 (s, 1 H) 7.49 -7.55 (m, 1 H) 7.62 - 7.70 (m, 1 H) 7.92 (d, J=2.93 Hz, 1 H) 8.22 (s, 1H) 9.14 (s, 1 H). LCMS (ESI) 455 (M + H).

Example 85 Synthesis of Compound 85

Compound 85 was synthesized in a similar manner to that described forcompound 78 followed by the deblocking step described for compound 65and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 3.21(s, 4 H) 3.35 - 3.67 (m, 5 H) 4.07 - 4.20 (m, 2 H) 6.13 (s, 1 H) 6.90(d, J=7.32 Hz, 2 H) 7.22 - 7.31 (m, 3 H) 7.36 (s, 1 H) 7.48 (d, J=9.37Hz, 1 H) 7.93 (d, J=2.34 Hz, 1 H) 8.04 - 8.11 (m, 1 H) 8.25 (d, J=4.98Hz, 1 H) 9.17 (s, 1 H) 11.77 (br, s., 1H). LCMS (ESI) 441 (M + H).

Example 86 Synthesis of Compound 86

Compound 86 was synthesized in a similar manner to that described forcompound 78 followed by the deblocking step described for compound 65and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.90(d, J=6.15 Hz, 6 H) 1.72 - 1.89 (m, 1 H) 3.15 - 3.92 (m, 9 H) 4.10 -4.46 (m, 2 H) 7.18 (s, 1 H) 7.59 (d, J=8.78 Hz, 1 H) 8.00 (s, 1 H) 8.13(d, J=9.37 Hz, 1 H) 8.55 (s, 1 H) 9.09 (s, 1 H) 9.67 (s, 2 H) 11.91 (s,1 H). LCMS (ESI) 407 (ESI).

Example 87 Synthesis of Compound 87

Compound 87 was synthesized in a manner similar to compound 86 and wasconverted to an HC1 salt. The characterization data (NMR and LCMS) wassimilar to that obtained for the antipode compound 86 .

Example 88 Synthesis of Compound 88

Compound 88 was synthesized in a similar manner to that described forcompound 78 followed by the deblocking step described for compound 65and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.78(s, 6 H) 3.40 - 3.53 (m, 6 H) 3.64 - 3.73 (m, 4 H) 7.27 (s, 1 H) 7.66(d, J=9.37 Hz, 1 H) 7.98 (d, J=2.34 Hz, 1 H) 8.12 (br. s., 1 H) 8.47(br. s., 1 H) 9.11 (s, 1 H) 9.45 (br. s., 2 H) 11.62 (br. s., 1 H). LCMS(ESI) 393 (M + H).

Example 89 Synthesis of Compound 89 (Also Referred to as Compound T)

Compound 89 was synthesized in a similar manner to that described forcompound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δppm 1.47 (br. s., 6 H) 1.72 (br. s., 2 H) 1.92 (br. s., 2 H) 2.77 (br.s., 3 H) 3.18 (br. s., 2 H) 3.46 (br. s., 2 H) 3.63 (br. s., 2 H) 3.66(d, J=6.15 Hz, 2 H) 3.80 (br. s., 2 H) 7.25 (s, 1 H) 7.63 (br. s., 2 H)7.94 (br. s., 1 H) 8.10 (br. s., 1 H) 8.39 (br. s., 1 H) 9.08 (br. s., 1H) 11.59 (br. s., 1 H). LCMS (ESI) 447 (M + H).

Example 90 Synthesis of Compound 90 (Also Referred to as Compound Q)

Compound 90 was synthesized in a similar manner to that described forcompound 78 followed by the deblocking step described for compound 65and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.27 -1.64 (m, 6 H) 1.71 (br. s., 2 H) 1.91 (br. s., 2 H) 2.80 (br. s., 1 H)3.17 - 3.24 (m, 2 H) 3.41 (br. s., 4 H) 3.65 (br. s., 4 H) 7.26 (br. s.,1 H) 7.63 (br. s., 1 H) 7.94 (br. s., 1 H) 8.13 (br. s., 1 H) 8.40 (br.s., 1 H) 9.09 (br. s., 1 H) 9.62 (br. s., 1 H) 11.71 (br. s., 1 H). LCMS(ESI) 433 (M + H).

Example 91 Synthesis of Compound 91 (Also Referred to as Compound ZZ)

Compound 91 was synthesized using similar conditions to those describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.64 - 1.75 (m, 2 H) 1.83 - 1.92 (m, 2 H) 1.96 - 2.06 (m,2 H) 2.49 - 2.58 (m, 2 H) 2.79 (d, 7=3.81 Hz, 3 H) 3.06 - 3.18 (m, 4 H)3.59 - 3.69 (m, 2 H) 3.73 - 3.83 (m, 2 H) 4.04 - 4.12 (m, 2 H) 7.17 (br.s., 1 H) 7.60 - 7.70 (m, 2 H) 7.70 - 7.92 (m, 2 H) 7.96 (br. s., 1 H)8.41 (br. s., 1 H) 8.98 (br. s., 1 H) 10.77 (br. s., 1 H). LCMS (ESI)433 (M + H).

Example 92 Synthesis of Compound 92

Compound 92 was synthesized in a similar manner to that described forcompound 78 followed by the deblocking step described for compound 65and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.64 -1.75 (m, 2 H) 1.84 - 1.92 (m, 2 H) 1.96 - 2.05 (m, 2 H) 2.48 - 2.56 (m,2 H) 3.22 (br. s., 4 H) 3.42 - 3.48 (m, 4 H) 3.60 - 3.69 (m, 2 H) 4.05 -4.13 (m, 1 H) 7.18 (s, 1 H) 7.65 (d, J=13.47 Hz, 1 H) 7.70 - 7.77 (m, 1H) 7.94 (d, J=1.76 Hz, 1 H) 8.42 (br. s., 1 H) 9.00 (s, 1 H) 9.15 (br.s., 2 H). LCMS (ESI) 419 (M + H).

Example 93 Synthesis of Compound 93

Compound 93 was synthesized in a similar manner to that described forcompound 78 followed by the deblocking step described for compound 65and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm 1.76(br. s., 2 H) 1.89 (br. s., 2 H) 2.03 (br. s., 2 H) 2.47 -2.58 (m, 2 H)3.04 (s, 3 H) 3.22 (br. s., 4 H) 3.39 (br. s., 4 H) 3.66 (s, 2 H) 7.21(s, 1 H) 7.67 (d, J=9.37 Hz, 1 H) 7.93 (br. s., 1 H) 7.98 - 8.09 (m, 1H) 9.04 (s, 1 H) 9.34 (br. s., 2 H) 11.31 (br. s., 1 H). LCMS (ESI) 433(M + H).

Example 94 Synthesis of Compound 94

Compound 94 was synthesized using similar conditions to that describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.66 - 1.77 (m, 2 H) 1.84 - 1.94 (m, 2 H) 1.96 - 2.08 (m,2 H) 2.48 - 2.57 (m, 2 H) 3.36 - 3.52 (m, 4 H) 3.60 - 3.80 (m, 6 H) 7.21(s, 1 H) 7.53 - 7.74 (m, 2 H) 7.86 (s, 1 H) 8.02 (s, 1 H) 8.45 (s, 1 H)9.03 (s, 1H) 11.19 (br. s., 1 H). LCMS (ESI) 420 (M+H).

Example 95 Synthesis of Compound 95

Compound 95 was synthesized using similar conditions to that describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.65 - 1.79 (m, 2 H) 1.85 - 1.95 (m, 2 H) 1.97 - 2.08 (m,2 H) 2.47 - 2.54 (m, 2 H) 3.40 - 3.58 (m, 5 H) 3.65 (dd, J=21.67, 5.56Hz, 1 H) 3.69 - 3.78 (m, 4 H) 7.24 (s, 1 H) 7.97 - 8.17 (m, 2 H) 8.48(s, 1 H) 9.08 (s, 1 H) 11.81 (s, 1 H). LCMS (ESI) 421 (M+H).

Example 96 Synthesis of Compound 96

Compound 96 was synthesized using similar conditions to that describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.55 - 1.74 (m, 2 H) 1.80 - 1.98 (m, 4 H) 2.48 - 2.60 (m,2 H) 3.40 - 3.50 (m, 4 H) 3.57 - 3.72 (m, 2 H) 3.90 - 4.20 (m, 4 H) 7.08(s, 1 H) 7.37 - 7.57 (m, 2 H) 7.70 (m, 2 H) 8.32 (s, 1 H) 8.88 (s, 1 H)9.98 (s, 1 H). LCMS (ESI) 419 (M+H).

Example 97 Synthesis of Compound 97 (Also Referred to as Compound III)

Compound 97 was synthesized using similar conditions to that describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.30 (d, J=5.27 Hz, 6 H) 1.65 - 1.78 (m, 2 H) 1.83 - 1.95(m, 2 H) 1.97 - 2.10 (m, 2 H) 2.45 - 2.55 (m, 2H) 3.25 - 3.36 (m, 1 H)3.39 - 3.48 (m, 4 H) 3.60 - 3.70 (m, 4 H) 3.75 - 4.15 (m, 2 H) 7.24 (s,1 H) 7.54 - 7.75 (m, 2 H) 7.95 (s, 1 H) 8.10 (s, 1 H) 8.49 (s, 1 H) 9.07(s, 1 H) 11.25 (s, 1 H) 11.48 (s, 1 H). LCMS (ESI) 461 (M+H).

Example 98 Synthesis of Compound 98

Compound 98 was synthesized using similar conditions to that describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 0.99 (d, J=6.15 Hz, 6 H) 1.65 - 1.78 (m, 2 H) 1.90 (m, 2H) 1.97 - 2.08 (m, 2 H) 2.08 - 2.17 (m, 1 H) 2.45 - 2.55 (m, 2H) 2.88 -3.02 (m, 2 H) 3.33 - 3.48 (m, 4 H) 3.50 - 3.90 (m, 6 H) 7.24 (s, 1 H)7.67 (s, 2 H) 7.94 (s, 1 H) 8.12 (s, 1 H) 8.49 (s, 1 H) 9.07 (s, 1 H)10.77 (s, 1 H) 11.51 (s, 1 H). LCMS (ESI) 475 (M+H).

Example 99 Synthesis of Compound 99

Compound 99 was synthesized using similar conditions to those describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.13 (d, J=5.86 Hz, 6 H) 1.66 - 1.77 (m, 2 H) 1.84 - 1.94(m, 2 H) 1.97 - 2.09 (m, 2 H) 2.40 - 2.53 (m, 2 H) 3.37 - 3.49 (m, 2 H)3.50 - 3.59 (m, 2 H) 3.59 - 3.73 (m, 4 H) 7.23 (s, 1 H) 7.64 (m, 3 H)7.85 (s, 1 H) 8.11 (s, 1 H) 8.47 (s, 1 H) 9.05 (s, 1 H). 11.35 (br s.,1H). LCMS (ESI) 448 (M+H).

Example 100 Synthesis of Compound 100

Compound 100 was synthesized using similar conditions to that describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.50 - 1.57 (m, 2 H) 1.62 - 1.68 (m, 3 H) 1.68 - 1.75 (m,2 H) 1.84 - 1.92 (m, 2 H) 1.97 - 2.08 (m, 2 H) 2.48 - 2.53 (m, 2 H)3.14 - 3.23 (m, 4 H) 3.43 - 3.47 (m, 2 H) 3.58 - 3.70 (m, 2 H) 7.22 (s,1 H) 7.58 - 7.70 (m, 2 H) 7.85 - 8.00 (m, 1 H) 8.16 (d, 1 H) 8.46 (s, 1H) 9.04 (s, 1 H) 11.37 (br s., 1H). LCMS (ESI) 418 (M + H).

Example 101 Synthesis of Compound 101 (Also Referred to as Compound WW)

Compound 101 was synthesized using similar conditions to those describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.72 (s, 2 H) 1.90 (s, 4 H) 2.03 (s, 2 H) 2.21 (s, 2 H)2.48 - 2.54 (m, 2 H) 2.73 (s, 2 H) 3.03 (s, 2 H) 3.25 - 3.35 (m, 1 H)3.38 - 3.48 (m, 4 H) 3.65 - 3.99 (m, 5 H) 7.23 (s, 1 H) 7.63 (d, J=9.66Hz, 1 H) 7.90 (s, 1 H) 8.13 (s, 1 H) 8.47 (s, 1 H) 9.06 (s, 1 H) 10.50(br s., 1H). LCMS (ESI) 503 (M + H).

Example 102 Synthesis of Compound 102 (Also Referred to as Compound HHH)

Compound 102 was synthesized using similar conditions to those describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.63 - 1.85 (m, 6 H) 1.87 - 1.92 (m, 2 H) 1.99 - 2.06 (m,2 H) 2.15 - 2.23 (m, 2 H) 2.47 - 2.53 (m, 1 H) 2.69 - 2.79 (m, 2 H)2.81 - 2.91 (m, 2 H) 2.98 - 3.08 (m, 2 H) 3.32 - 3.48 (m, 4 H) 3.57 -3.72 (m, 4 H) 3.77 - 3.85 (m, 2 H) 7.22 (s, 1 H) 7.60 - 7.68 (m, 2 H)7.90 (s, 1 H) 8.07 (s, 1 H) 8.46 (s, 1 H) 9.04 (s, 1 H). 11.41 (br s.,1H). LCMS (ESI) 501 (M + H).

Example 103 Synthesis of Compound 103

Compound 103 was synthesized using similar conditions to those describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.64 - 1.76 (m, 2 H) 1.87 - 1.93 (m, 2 H) 2.00 - 2.07 (m,2 H) 2.48 - 2.53 (m, 2 H) 2.67 - 2.72 (m, 4 H) 3.44 - 3.47 (m, 2 H)3.50 - 3.55 (m, 4 H) 7.24 (s, 1 H) 7.61 (d, J=9.37 Hz, 2 H) 7.86 (d,J=2.63 Hz, 1 H) 8.09 (d, J=12.88 Hz, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H)11.41 (br s., 1H). LCMS (ESI) 436 (M + H).

Example 104 Synthesis of Compound 104

Compound 104 was synthesized using similar conditions to those describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.29 (d, J=6.73 Hz, 6 H) 1.66 - 1.79 (m, 2 H) 1.84 - 1.95(m, 2 H) 1.98 - 2.09 (m, 2 H) 2.46 - 2.55 (m, 2 H) 3.29 -3.39 (m, 2H)3.58 - 3.70 (m, 4H) 3.77 - 3.86 (m, 4H) 7.24 (s, 1 H) 7.66 (d, J=9.37Hz, 1 H) 7.96 (d, J=2.93 Hz, 1 H) 8.08 (s, 1 H) 8.48 (s, 1 H) 9.06 (s, 1H) 9.28 (s, 1 H) 9.67 (s, 1 H) 11.36 (s, 1H). LCMS (ESI) 447 (M + H).

Example 105 Synthesis of Compound 105

Compound 105 was synthesized using similar conditions to those describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.73 (s, 2 H) 1.76 -1.85 (m, 2 H) 1.85 - 1.94 (m, 2 H)1.98 - 2.07 (m, 2 H) 2.19 - 2.26 (m, 2 H) 2.48 - 2.52 (m, 1 H) 2.70 -2.81 (m, 4 H) 3.13 - 3.20 (m, 1 H) 3.30 - 3.48 (m, 3 H) 3.58 - 3.71 (m,4 H) 3.78 - 3.84 (m, 4 H) 7.24 (s, 1 H) 7.62 (d, J=9.37 Hz, 2 H) 7.89(d, J=1.17 Hz, 1 H) 8.09 - 8.18 (m, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H)11.46 (br s., 1H). LCMS (ESI) 519 (M + H).

Example 106 Synthesis of Compound 106

Compound 106 was synthesized using similar conditions to those describedfor compound 78 followed by the deblocking step described for compound65 and was converted to an HC1 salt. ¹HNMR (600 MHz, DMSO-d₆) δ ppm1.65 - 1.75 (m, 2 H) 1.85 - 1.93 (m, 2 H) 1.93 - 1.99 (m, 1 H) 2.00 -2.06 (m, 2 H) 2.08 - 2.14 (m, 1 H) 2.47 - 2.55 (m, 2 H) 3.07 - 3.25 (m,2 H) 3.25 - 3.69 (m, 5 H) 4.46 (s, 1 H) 4.67 (s, 1 H) 7.22 (s, 1 H)7.58 - 7.69 (m, 2 H) 8.46 (s, 1 H) 9.02 (s, 1 H) 9.34 (s, 1 H) 9.65 (s,1 H). LCMS (ESI) 431 (M + H).

Example 107 Synthesis of Compound 107 (Also Referred to as Compound YY)

Compound 107 was synthesized using similar conditions to those describedfor compound 78 and was converted to an HC1 salt. ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.65 - 1.82 (m, 3 H) 1.89 (br. s., 2 H) 1.98 - 2.08 (m, 2H) 2.13 (br. s., 2 H) 2.47 - 2.55 (m, 2 H) 2.68 (d, J=4.98 Hz, 6 H)2.71 - 2.80 (m, 2 H) 3.29 - 3.71 (m, 10 H) 7.16 - 7.26 (m, 1 H) 7.67 (d,J=9.66 Hz, 2 H) 7.91 (d, J=2.05 Hz, 1 H) 8.14 (br. s., 1 H) 8.48 (br.s., 1 H) 9.05 (s, 1 H) 11.14 (br. s., 1 H) 11.43 (br. s., 1 H). LCMS(ESI) 461 (M + H).

Example 108 Synthesis of Compound 108

Compound 108 was synthesized in a manner similar to that described forcompounds 64 and 65 and was recovered as an HC1 salt. The analyticaldata was consistent with that described for the antipode compound 75 .

Example 109 Synthesis of Compound 109

Compound 109 was synthesized in a manner similar to that described forcompounds 64 and 65 and was recovered as an HC1 salt. The analyticaldata was consistent with that described for the antipode compound 75.

Example 110 Synthesis of Compound 110

Compound 110 was synthesized in a similar manner to that described forcompound 78 and then converted to its hydrochloride salt. ¹HNMR (600MHz, DMSO-d₆) δ ppm 1.50 - 1.65 (m, 1 H) 1.92 - 2.02 (m, 3 H) 2.06 -2.15 (m, 1 H) 2.78 (d, J=3.81 Hz, 4 H) 3.10 - 3.20 (m, 4 H) 3.47 - 3.51(m, 2 H) 3.64 - 3.71 (m, 1 H) 3.76 - 3.83 (m, 2 H) 3.98 - 4.14 (m, 1 H)7.20 (s, 2 H) 7.77 (s, 1 H) 7.97 (s, 2 H) 8.81 (s, 1 H) 9.03 (s, 1 H)10.97 (br s., 1H). LCMS (ESI) 419 (M + H).

Example 111 Synthesis of Compound 111

Compound 111 was synthesized in a similar manner to that described forcompound 78 and then converted to its hydrochloride salt. ¹HNMR (600MHz, DMSO-d₆) δ ppm 1.54 - 1.59 (m, 1 H) 1.92 - 2.01 (m, 3 H) 2.06 -2.15 (m, 1 H) 2.76 - 2.84 (m, 1 H) 3.17 - 3.24 (m, 6 H) 3.64 -3.71 (m, 2H) 4.02 - 4.11 (m, 2 H) 7.22 (s, 2 H) 7.64 (s, 1 H) 7.97 (s, 2 H) 8.75(s, 1 H) 8.97 (s, 1 H) 9.21 (s, 1 H). LCMS (ESI) 405 (M + H).

Example 112 Synthesis of Compound 112

Compound 112 was synthesized using similar experimental conditions tothat described for compound 64.

Example 113 Synthesis of Tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate, Compound113

To a solution of 5-bromo-2,4-dichloropyrimidine (12.80 g, 0.054 mole) inethanol (250 mL) was added Hunig’s base (12.0 mL) followed by theaddition of a solution of N-(tert-butoxycarbonyl)-1,2-diaminoethane (10g, 0.0624 mole) in ethanol (80 mL). The contents were stirred overnightfor 20 hrs. The solvent was evaporated under vacuum. Ethyl acetate (800mL) and water (300 mL) were added and the layers separated. The organiclayer was dried with magnesium sulfate and then concentrated undervacuum. Column chromatography on silica gel using hexane/ethyl acetate(0- 60%) afforded tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI)351 (M + H).

Example 114 Synthesis of Tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate, Compound 114

To tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (5 g, 14.23mmole) in toluene (42 mL) and triethylamine (8.33 mL) under nitrogen wasadded triphenyl arsine (4.39 g), 3,3-diethoxyprop-1-yne (3.24 mL) andPddba (1.27 g). The contents were heated at 70 degrees for 24 hrs. Afterfiltration through CELITE®, the crude reeacton was columned usinghexane/ethyl acetate (0- 20%) to afford the desired product 3.9 g).Column chromatography of the resulting residue using hexane/ethylacetate (0- 30%) afforded tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate.LCMS (ESI) 399 (M + H).

Example 115 Synthesis of Tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate,Compound 115

To a solution of Compound 114 (3.9 g, 0.00976 mole) in THF (60 mL) wasadded TBAF (68.3 mL, 7eq). The contents were heated to 45 degrees for 2hrs. Concentration followed by column chromatography using ethylacetate/hexane (0-50%) afforded tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamateas a pale brown liquid (1.1 g). ¹HNMR (d6-DMSO) 6 ppm 8.88 (s, 1H), 6.95(brs, 1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29 (m, 2H), 3.59 (m, 4H), 3.34(m, 1H), 3.18 (m, 1H), 1.19 (m, 9H), 1.17 (m, 6H). LCMS (ESI) 399 (M+H).

Example 116 Synthesis of Tert-butylN-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate,Compound 116

To tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate(0.1 g, 0.00025 mol) in acetonitrile (2 mL) was added1,3-diiodo-5,5-dimethylhydantoin (95 mg, 1 eq), and solid NaHCOs (63 mg,3 eq). The reacation was stirred at room tempreature for 16 hrs. Thereaction was filtered and concentrated in vacuo. The product waspurified by silica gel column chromatography using hexane/ethyl acetate(0 - 50%) to afford tert-butylN-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamateas a pale yellow solid (0.03 g). LCMS (ESI) 525 (M + H).

Example 117 Synthesis of tert-ButylN-[2-[2-chloro-6-(diethoxymethyl)-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate,Compound 117

To tert-butylN-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate(0.1 g, 0.19 mmole) in dioxane (3 mL) was added 2-methylphenylboronicacid (28 mg), tetrakis(triphenylphosphine)palladium (25 mg) andpotassium phosphate (250 mg) in water (0.3 mL). The reaction was heatedin a CEM Discovery microwave at 90° C. for 3 hrs. The crude reaction wasloaded onto silica gel and columned using hexane/ethyl acetate (0 -30%)to afford tert-butylN-[2-[2-chloro-6-(diethoxymethyl)-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate(0.06 g). LCMS (ESI) 489 (M + H).

Example 118 Synthesis of7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicAcid, Compound 118

To tert-butylN-[2-[2-chloro-6-(diethoxymethyl)-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate(0.85 g, 1.74 mmole) in AcOH (10 mL) was added water (1.5 mL). Thereation was stirred at room tempreature for 16 hrs. The crude reactionwas then concentrated under vacuum. After the addition of ethyl acetate(50 mL), the organic layer was washed with satd. NaHCO₃. The organiclayer was dried with magnesium sulfate and then concentrated undervacuum to afford the crude intermediate, tert-butylN-[2-[2-chloro-6-formyl-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate.To this crude intermediate in DMF (5 mL) was added oxone (1.3 g). Afterstirring for 2.5 hrs, water (20 mL) and ethyl acetate (100 mL) wereadded. The organic layer was separated, dried and then concentratedunder vacuum to afford the crude product which was columned over silicagel using hexane/ethyl acetate (0 - 50%) to afford7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid (0.112 g). LCMS (ESI) 431 (M + H).

Example 119 Synthesis of Compoound 119

To7-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid (0.1 g, 0.261 mmol) in DCM (4.1 mL) was added DMAP (20 mg) followedby the addition of N,N′-diisopropylcarbodiimide (0.081 mL, 2eq). Afterstirring for 3 hrs, TFA (0.723 mL) was added. Stirring was thencontinued for another 30 minutes. The reaction mixture was neutralizedwith satd. NaHCO₃. DCM (20 mL) was then added and the organic layerseparated, dried with magnesium sulfate and then concentrated undervacuum to afford the crude product which was columned using hexane/ethylacetate (0-100%) to afford chloro tricyclic amide Compound 119 (0.65 g).LCMS (ESI) 313 (M + H).

Example 120 Synthesis of Compound 120

To the chloro tricyclic amide (0.040 g, 0.128 mmole) (Compound 119) indioxane (2.5 mL) under nitrogen was added Pd₂(dba)₃ (12 mg), sodiumtert-butoxide (16 mg), BINAP (16 mg) and 4-morpholinoaniline (22.7 mg,1eq). The reaction mixture was heated at 90° C. in a CEM Discoverymicrowave for 3.0 hrs. The crude reaction was loaded onto a silica gelcolumn and the contents eluted with DCM/MeOH (0-6%) to afford theproduct (10 mg). LCMS (ESI) 455 (M + H). ¹HNMR (600 MHz, DMSO-d₆) δ ppm2.14 (s, 3 H) 3.23 - 3.50 (m, 2 H) 3.57 - 3.73 (m, 2 H), 3.81 - 3.92 (m,8H), 7.11 - 7.31 (m, 4 H) 7.31 - 7.48 (m, 1 H) 7.58 - 7.73 (m, 1 H)7.77 - 7.95 (m, 2 H) 8.05 - 8.21 (m, 1 H) 8.44 (s, 1 H) 9.85 - 10.01 (m,1 H).

Example 121 Synthesis of Compound 121

To the chloro tricyclic amide (0.024 g) (Compound 119) inN-methyl-2-pyrrolidone (NMP) (1.5 mL) was addedtrans-4-aminocyclohexanol (0.0768 mmol, 26.54 mg, 3 eq) and Hunig’s base(0.4 mL). The reaction was heated in a CEM Discovery microwave vessel at150° C. for 1.2 hrs. The crude reaction was loaded onto a silica gelcolumn and the contents eluted with DCM/MeOH (0 - 10%) to afford theproduct (21 mg). LCMS (ESI) 392 (M + H). ¹HNMR (600 MHz, DMSO-d₆) δ ppm1.23 (d, J=8.78 Hz, 4 H) 1.84 (br. s., 4 H) 2.11 (s, 3 H) 3.34 - 3.43(m, 1 H) 3.55 (br. s., 2 H) 3.72 (br. s., 1 H) 4.13 (br. s., 2 H) 4.50(br. s., 1 H) 7.03 (br. s., 1 H) 7.12 - 7.28 (m, 4 H) 7.96 (br. s., 1 H)8.18 (br. s., 1 H).

Example 122 Synthesis of7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicAcid, Compound 122

7-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using a similar experimental procedure as thatdescribed for the synthesis of7-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. LCMS (ESI) 341 (M + H).

Example 123 Synthesis of Compound 123

Chloro tricyclic amide, Compound 123, was synthesized using a similarexperimental procedure as that described for the synthesis of chlorotricyclic amide (Compound 119). LCMS (ESI) 223 (M + H).

Example 124 Synthesis of Compound 124

To the chloro tricyclic amide, Compound 123 (0.035 g, 0.00157 mole) inNMP (1.5 mL) was added Hunig’s base (0.3 mL) followed by the addition ofthe trans-4-aminocyclohexanol (54.2 mg). The reaction mixture was heatedat 150° C. for 1.5 hrs. The crude reaction was loaded onto a silica gelcolumn and the column was eluted with DCM/MeOH (0 - 10%) to afford theproduct (5 mg). LCMS (ESI) 302 (M + H).

Example 125 Synthesis of Tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methylpropyl]carbamate,Compound 125

tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamatewas synthesized by treating 5-bromo-2,4-dichloropyrimidine withtert-butyl N-(2-amino-2-methyl-propyl)carbamate using similarexperimental conditions as described for the synthesis of tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI)(M+H) 379.

Example 126 Synthesis of Tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamate,Compound 126

tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methylpropyl]carbamatewas synthesized by treating tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamatewith 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddbausing similar experimental conditions as described for the synthesis oftert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate.

LCMS (ESI) (M+H) 427.

Example 127 Synthesis of Tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-methyl-propyl]carbamate,Compound 127

tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-methylpropyl]carbamatewas synthesized by treating tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamatewith TBAF using similar experimental conditions as described for thesynthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) (M+H) 427.

Example 128 Synthesis of7-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicAcid, Compound 128

7-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using a similar experimental procedure as thatdescribed for the synthesis of7-(tert-butoxycarbonylamino)ethyl]-2-chloro-5 -(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylic acid. LCMS (ESI) 369 (M + H).

Example 129 Synthesis of Compound 129

Chloro tricyclic amide, Compound 129, was synthesized using a similarprocedure as that described for the synthesis of chloro tricyclic amide,Compound 119. LCMS (ESI) 251 (M + H).

Example 130 Synthesis of Compound 130

Compound 130 was synthesized by treating chlorotricyclic amine Compound129 with trans-4-aminocyclohexanol using similar experimental conditionsas for compound 124. LCMS (ESI) 330 (M + H). ¹HNMR (600 MHz, DMSO-d₆) 6ppm 1.07 - 1.34 (m, 4 H) 1.47 - 2.05 (m, 10 H) 3.09 (m, 1H) 3.51 (d, J =2.91 Hz, 2 H) 3.57 (m, 1H) 4.50 (br. s., 1 H) 6.89 (s, 1 H) 6.94 - 7.05(m, 1 H) 8.04 (br. s., 1 H) 8.60 (s, 1 H) 9.00 (br. s., 1 H).

Example 131 Synthesis of BenzylN-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]carbamate,Compound 131

BenzylN-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]carbamatewas synthesized by treating 5-bromo-2,4-dichloropyrimidine with benzylN-[1-(aminomethyl)propyl]carbamate using similar experimental conditionsas described for the synthesis of tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI)(M+H) 413.

Example 132 Synthesis of BenzylN-[l-[[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]methyl]propyl]carbamate,Compound 132

BenzylN-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]propyl]carbamatewas prepared by treating benzylN-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]-carbamatewith 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddbausing similar experimental conditions as described for the synthesis oftert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]ethyl]carbamateLCMS (ESI) (M+H) 461.

Example 133 Synthesis of BenzylN-[1-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]propyl]carbamate, Compound 133

BenzylN-[1-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]propyl]carbamatewas synthesized by treating benzylN-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]propyl]carbamatewith TBAF using similar experimental conditions as described for thesynthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) (M+H) 461.

Example 134 Synthesis of7-[2-(benzyloxycarbonylamino)butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-CarboxylicAcid, Compound 134

7-(benzyloxycarbonylamino)butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using a similar experimental procedure as thatdescribed for the synthesis of7-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. LCMS (ESI) 403 (M + H).

Example 135 Synthesis of Compound 135

To a solution of7-[2-(benzyloxycarbonylamino)butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid in dichloromethane was added HBr, the reaction was stirred at 45degrees for 3 hrs. After concentration, 2N NaOH was added to basify (pH= 8.0) the reaction followed by the addition of THF (20 mL). Boc₂O wasthen added (1.2 eq) and the reacation was stirred for 16 hrs. To thecrude reaction mixture was then added ethyl acetate (100 mL) and water(50 mL) and the organic phase was separated, dried (magnesium sulfate)and then concentrated under vacuum. To the crude product was addeddichloromethane (30 mL) followed by DIC and DMAP. After stirring for 2hrs, TFA was added and the contents stirred for an hour. The solventswere evaporated under vacuum and the residue basified with satd. NaHCO₃.Ethyl acetate was then added and the organic layer separated, dried(magnesium sulfate) and then concentrared under vacuum. Columchromatography with hexane/ethyl acetate (0 -100%) afforded the desiredchlorotricyclic core, Compound 135. LCMS (ESI) 251 (M + H).

Example 136 Synthesis of Compound 136

Compound 136 was synthesized by treating chlorotricyclic amine, Compound135, with trans-4-aminocyclohexanol using similar experimentalconditions as for compound 124. LCMS (ESI) 330 (M + H). ¹HNMR (600 MHz,DMSO-d₆) δ ppm 0.80 - 0.95 (m, 3 H) 1.35 - 1.92 (m, 10 H) 3.66 (br. m.,3 H) 4.17 (br. s., 2 H) 4.47 (br. s., 1 H) 6.85 (s, 1 H) 6.96 (br. s., 1H) 8.15 (br. s., 1 H) 8.62 (br. s., 1 H).

Example 137 Synthesis of Tert-butylN-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamate,Compound 137

tert-butylN-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamatewas synthesized by treating 5-bromo-2,4-dichloropyrimidine withtert-butyl N-[1-(aminomethyl)cyclopentyl]carbamate using similarexperimental conditions as described for the synthesis of tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI)405 (M+H).

Example 138 Synthesis of Tert-butylN-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]cyclopentyl]carbamate,Compound 138

tert-butylN-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]cyclopentyl]carbamatewas synthesized by treating tert-butylN-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamatewith with 3,3-diethoxyprop-1-yne in the presence of a catalyst such asPddba using similar experimental conditions as described for thesynthesis of tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate LCMS (ESI) 453 (M+H).

Example 139 Synthesis of Tert-butylN-[l-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]cyclopentyl]carbamate,Compound 139

tert-butylN-[1-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]cyclopentyl]carbamatewas synthesized by treating tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamatewith TBAF using similar experimental conditions as described for thesynthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) 453 (M+H).

Example 140 Synthesis of7-[[1-(tert-butoxycarbonylamino)cyclopentyl]methyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicAcid, Compound 140

7-[(tert-butoxycarbonylamino)cyclopentyl]methyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using a similar experimental procedure as thatdescribed for the synthesis of7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. LCMS (ESI) 395 (M + H).

Example 141 Synthesis of Compound 141

Chlorotricyclic core Compound 141 was synthesized using a similarexperimental procedure as that described for the synthesis of chlorotricyclic amide Compound 119. LCMS (ESI) 277 (M + H).

Example 142 Synthesis of Compound 142

Compound 142 was synthesized by treating chlorotricyclic amine, Compound141, with trans-4-aminocyclohexanol using similar experimentalconditions as for Compound 124 . LCMS (ESI) 356 (M + H). ¹HNMR (600 MHz,DMSO-d₆) δ ppm 1.08 - 1.32 (m, 8 H) 1.60 - 2.09 (m, 8 H) 3.03 - 3.17 (m,1 H) 3.35 (s, 2 H) 3.54 - 3.62 (m, 1 H) 4.51 (d, J=4.39 Hz, 1 H) 6.88(s, 1 H) 6.96 (br. s., 1 H) 8.07 (br. s., 1 H) 8.58 (s, 1 H).

Example 143 Synthesis of Tert-butylN-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamate,Compound 143

tert-butylN-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamatewas synthesized by treating 5-bromo-2,4-dichloropyrimidine withtert-butyl N-[(1-aminocyclopentyl)methyl]carbamate using similarexperimental conditions as described for the synthesis of tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI)405 (M+H).

Example 144 Synthesis of Tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamate,Compound 144

tert-butylN-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]methyl]carbamatewas synthesized by treating tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamatewith 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddbausing similar experimental conditions as described for the synthesis oftert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate.

LCMS (ESI) 453 (M+H).

Example 145 Synthesis of Tert-butylN-[[1-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]methyl]carbamate,Compound 145

tert-ButylN-[[1-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]methyl]carbamatewas synthesized by treating tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamatewith TBAF using similar experimental conditions as described for thesynthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) 4534 (M+H).

Example 146 Synthesis of7-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6carboxylicAcid, Compound 146

7-(tert-Butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using a similar experimental procedure as thatdescribed for the synthesis of7-(tert-butoxycarbonylamino)ethyl]-2-chloro-5 -(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylic acid. LCMS (ESI) 395 (M + H).

Example 147 Synthesis of Compound 147

Chloro tricyclic amide, Compound 147 was synthesized using a similarexperimental procedure as that described for the chloro tricyclic amide,Compound 119. LCMS (ESI) 277 (M + H).

Example 148 Synthesis of Compound 148

Compound 148 was synthesized by treating chlorotricyclic amine, Compound147, with trans-4-aminocyclohexanol using similar experimentalconditions as for Compound 124. LCMS (ESI) 356 (M + H). ¹HNMR (600 MHz,DMSO-d₆) 6 ppm 1.06 - 1.35 (m, 8 H) 1.45 - 1.95 (m, 8 H) 3.10 (m, 1 H)3.58 (br. s., 2 H) 3.95 (br. s., 1 H) 4.49 (br. s., 1 H) 6.84 (s, 1 H)6.85 - 6.93 (m, 1 H) 8.29 (s, 1 H) 8.61 (br. s., 1 H).

Example 149 Synthesis of Compound 149

Step 1: Compound 59 is Boc protected according to the method of A.Sarkar et al. (JOC, 2011, 76, 7132-7140).

Step 2: Boc-protected Compound 59 is treated with 5 mol% NiCl2(Ph₃)₂,0.1 eq triphenylphosphine, 3 eq Mn, 0.1 eq tetraethylammonium iodide, inDMI under CO₂ (1 atm) at 25° C. for 20 hours to convert the aryl halidederivative into the carboxylic acid.

Step 3: The carboxylic acid from Step 2 is converted to thecorresponding acid chloride using standard conditions.

Step 4: The acid chloride from Step 3 is reacted with N-methylpiperazine to generate the corresponding amide.

Step 5: The amide from Step 4 is deprotected using trifluoroacetic acidin methylene chloride to generate the target compound. Compound 149 waspurified by silica gel column chromatography eluting with adichloromethane - methanol gradient to provide Compound 149.

Each of Compounds 119 through 147 and corresponding compounds withvarious R⁸, R¹ and Z definitions may be reacted with sodium hydride andan alkyl halide or other halide to insert the desired R substitutionprior to reaction with an amine, such as described above for thesynthesis of Compound 120, to produce the desired product of Formulae I,II, III, IV, or V.

Example 150 Inhibition of Cellular Proliferation

FIG. 9 is a graph showing the cellular proliferation of SupT1 cells(human T-cell lymphoblastic leukemia) treated with PD0332991 (circles)or Compound T (Table 1; squares). FIG. 10 is a graph showing thecellular proliferation of SupT1 cells (human T-cell lymphoblasticleukemia) treated with Compound Q (Table 1; circles) or Compound GG(Table 1; squares). The SupT1 cells were seeded in Costar (Tewksbury,Massachusetts) 3093 96 well tissue culture treated white walled/ clearbottom plates. A nine point dose response dilution series from 10 uM to1 nM was performed and cell viability was determined after four days asindicated using the CellTiter-Glo® assay (CTG; Promega, Madison,Wisconsin, United States of America) following the manufacturer’srecommendations. Plates were read on a BioTek (Winooski, Vermont)Syngergy2 multi-mode plate reader. The Relative Light Units (RLU) wereplotted as a result of variable molar concentration and data wasanalyzed using Graphpad (LaJolla, California) Prism 5 statisticalsoftware to determine the IC50 for each compound.

Example 151 Inhibition of Cellular Proliferation in T-Cell and B-CellSpecific Cancer Cells

The compounds listed in Table 1 were tested for the inhibition ofcellular proliferation using Sup T1 (human T-cell lymphoblasticleukemia) and Daudi (human B- lymphoblastoid cell from Burkitt’sLymphoma patient). FIGS. 9 and 10 and Example 150 illustrate how theECsos were measured.

Most of the compounds tested showed significant inhibition of the SupT1T-cell lymphoblastic leukemia cell line. The range for the EC₅₀ of thecompounds tested that were necessary for inhibition of SupT1 T-celllymphoblastic leukemia cell proliferation was 9.3 nM to 3037 nM. Many ofthe compounds also had significant effects on the inhibition of theB-cell lymphoblastoid cell line (Daudi). The range for the EC₅₀ of thecompounds tested that were necessary for inhibition of Daudi B-celllymphoblastoid cell proliferation was 111 nM to 3345 nM.

TABLE 2 Inhibition of Cellular Proliferation in Cancer Cells StructureSupT1 Cellular EC₅₀ [nM] Daudi Cellular EC₅₀ [nM] A 57 281 B 96 385 C 74373 D 55 297 E 9.3 140 F 107 692 G 156 1530 H 118 719 I 39 249 J 47 362K 134 167 L 153 1262 M 184 1455 N 34 122 O 44 123 P 33 140 Q 40 561 R 43299 S 110 634 T 113 392 U 48 363 V 35 194 W 57 731 X 36 318 Y 85 548 Z87 359 AA 58 233 BB 70 472 CC 17 111 DD 105 546 EE 89 259 FF 90 380 GG57 784 HH 79 681 II 42 347 JJ 49 389 KK 112 147 LL 84 501 MM 84 681 NN84 1042 OO 114 880 PP 81 260 QQ 68 851 RR 102 158 SS 11 967 TT 92 589 UU228 3163 VV 115 683 WW 77 1692 XX 94 499 YY 97 356 ZZ 272 584 AAA 153345 BBB 41 758 CCC 133 1865 DDD 161 839 EEE 65 475 FFF ND ND GGG 161586 HHH 85 984 III 230 775 JJJ 143 448 KKK ND ND LLL 241 1548 MMM 37 294NNN 160 519 OOO 104 668 PPP 3037 ND QQQ 258 485 RRR 278 2011 SSS305 >3000 TTT 587 3299 UUU 311 1425 VVV 224 1072 WWW 264 1266 XXX 2701170

We claim:
 1. A method of treating acute myelogenous leukemia (AML) in ahuman in need thereof comprising administering to the host an effectiveamount of a compound having the structure:

or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the compound, or its pharmaceutically acceptable salt thereof,is administered in combination with a second active agent.
 3. The methodof claim 1, wherein the AML is selected from undifferentiated AML,myeloblastic leukemia with minimal cell maturation, myeloblasticleukemia with cell maturation, promyelocytic leukemia, myelomonocyticleukemia, myelomonocytic leukemia with eosinophilia, monocytic leukemia,erythroleukemia, or megakaryoblastic leukemia.
 4. The method of claim 3,wherein the AML is undifferentiated AML.
 5. The method of claim 3,wherein the AML is myeloblastic leukemia with minimal cell maturation.6. The method of claim 3, wherein the AML is myeloblastic leukemia withcell maturation.
 7. The method of claim 3, wherein the AML ispromyelocytic leukemia.
 8. The method of claim 3, wherein the AML ismyelomonocytic leukemia.
 9. The method of claim 3, wherein the AML ismyelomonocytic leukemia with eosinophilia.
 10. The method of claim 3,wherein the AML is monocytic leukemia.
 11. The method of claim 3,wherein the AML is erythroleukemia.
 12. The method of claim 3, whereinthe AML is megakaryoblastic leukemia.
 13. A method of treating a B-celllymphoma in a human in need thereof comprising administering to the hostan effective amount of a compound having the structure:

or a pharmaceutically acceptable salt thereof.
 14. The method of claim13, wherein the compound, or its pharmaceutically acceptable saltthereof, is administered in combination with a second active agent. 15.The method of claim 13, wherein the B-cell lymphoma is selected fromdiffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, nodalmarginal zone B-cell lymphoma (NMZL), splenic marginal zone B-celllymphoma (SMZL), extranodal marginal zone mucosa-associated lymphoidtissue (MALT) B-cell lymphoma, intravascular large B-cell lymphoma,splenic diffuse red pulp small B-cell lymphoma, T cell/histocyte-richlarge B-cell lymphoma, primary mediastinal (thymic) large B-celllymphoma, ALK+ large B-cell lymphoma, large B-cell lymphoma arising inHHV8-associated multicentric Castleman disease, unclassifiable B-celllymphoma with features intermediate between diffuse large B-celllymphoma, unclassifiable B-cell lymphoma with features intermediatebetween diffuse large B-cell lymphoma and classical Hodgkin lymphoma.16. The method of claim 15, wherein the B-cell lymphoma is primarymediastinal B-cell lymphoma.
 17. The method of claim 15, wherein theB-cell lymphoma is extranodal marginal zone mucosa-associated lymphoidtissue (MALT) B-cell lymphoma.
 18. The method of claim 15, wherein theB-cell lymphoma is nodal marginal zone B-cell lymphoma (NMZL).
 19. Themethod of claim 15, wherein the B-cell lymphoma is splenic marginal zoneB-cell lymphoma (SMZL).
 20. A method of treating a multiple myeloma in ahuman in need thereof comprising administering to the host an effectiveamount of a compound having the structure:

or a pharmaceutically acceptable salt thereof.
 21. The method of claim20, wherein the compound, or its pharmaceutically acceptable saltthereof, is administered in combination with a second active agent.